Five membered heterocyclic compounds

ABSTRACT

The instant invention is related to 5-membered heterocyclic compounds and pharmaceutical compositions which possess inhibitory activity on 5 alpha-reductase.

This application is a 371 of PCT/US95/1962 filed Sep. 27, 1995.

SUMMARY

This invention is related to five membered heterocyclic compounds. Moreparticularly, this invention is related to:

(1) An inhibitory agent on 5α-reductase which comprises a five memberedheterocyclic compound of the formula (Ia): ##STR1## wherein all thesymbols are the same meaning as hereafter defined, and non-toxic saltsthereof as active ingredient,

(2) a five membered heterocyclic compound of the formula (Ib): ##STR2##wherein all the symbols are the same meaning as hereafter defined, andnon-toxic salts thereof,

(3) process for the preparation of a five membered heterocyclic ringcompound of the formula (Ib) and non-toxic salts thereof.

BACKGROUND

So far as the origin of androgenic alopecia, many theories are expositedsuch as (1) imbalance of hormones, (2) genetics, (3) circulatoryfailure, (4) nutrition. And it has been suggested that testosterone(androgenic hormone) played an important role on the generation ofhairs. The relation between testosterone and androgenic alopecia is asfollows:

(i) first, testosterone biosynthesized in testis is converted intodihydrotestosterone(DHT) by 5α-reductase existed in hair follicle,sebaceous gland etc. at the head,

(ii) DHT reduces the activities of adenyl cyclase remarkably,

(iii) it induces fall of the level of cyclic-AMP in cells,

(iv) last, it induces lowering of energy generation of hairs and thelimbus and suppressing of protein synthesis Biochem. Biophys. Res.Commun., 41,884(1970)!.

Large quantities of metabolites by 5α-reductase such as DHT etc. in hairfollicles of androgenic alopecia-patient exist more than that in femalesor healthy males. J. Clin. Endocr., 38, 811(1974)!.

It was reported that DHT converted from testosterone by 5α-reductasealso plays an important physiological role in the generation of acnes(acne, pimple etc.) other than androgenic alopecia Br. J. Dermatol., 91,123(1974); J. Invest. Dermatol., 56, 366(1971)!.

It has been clear that DHT also plays an important role in thegeneration and the development of prostatic hypertrophy J. SteroidBiochemistry, 11, 609(1979); J. Clinical Endocrinol and Metabolism, 56,139(1983)!.

And, it is thought that DHT is also related to prostatic cancer.

Recently, it was confirmed that the existence of at least two5α-reductase isozymes (I type and II type) in human. There aredifferences between these isozymes about gene formation, of course,biochemical properties, expression styles, hereditary properties andpharmacological properties. Nature, 354, 159-161(1991); J. Clin,Invest., 89,293-300(1992)!. Among two type isozymes, it is consideredthat II type one exists more than I type one in human testis.

Therefore, it was confirmed that inhibition of a change fromtestosterone to DHT by 5α-reductase inhibitor is useful for abovediseases.

Now, research and development of 5α-reductase inhibitors are carried outenergetically. Many kinds of compounds are synthesized and tested.5α-Reductase inhibitors are largely divided into compounds havingsteroidal structure and compounds having non-steroidal structure.

A representation of steroidal compound is finasteride, shown by belowformula, and the compound is available in the market. ##STR3##

As a non-steroidal compound, ONO-3805 shown below formula is known.##STR4##

RELATED ARTS

Non-steroidal compounds possessing 5α-reductase inhibitory activity, forexample, are the following:

(1) In the specification of WO9324442, benzoic acid derivatives aredisclosed.

(2) In the specification of European Patent Publication Number 458207,WO9303012, WO 9305019 and WO9316996, indole derivatives are disclosed.

(3) In the specification of European Patent Publication Number 519353,indolizine derivatives are disclosed.

(4) In the specification of WO9313099, the compound of the formula (A)is disclosed.

    R.sup.1A --A.sup.A --CO--X.sup.A --Y.sup.A --R.sup.2A      (A)

wherein R^(1A) is carboxy (lower) alkyl or protectedcarboxy(lower)alkyl, R^(2A) is optionally substituted aralkyl,

X^(A) is optionally substituted arylene,

Y^(A) is --O-- or --NR^(6A) --,

in which R^(6A) is hydrogen, lower alkyl, optionally substituted aralkylor amino-protective group, and

A^(A) is a bivalent radical derived from imidazopyridine, azulene,thiophene, pyrrolo 2,3-b!pyridine, quinolone, indazole ordihydrobenzimidazole, each of which may be substituted by one or moresuitable substituent(s).

(5) On the 24th National Medicinal Chemistry Symposium (Jun. 21-24,1994), it was discussed that benzoic acid derivatives and indolederivatives having 5α-reductase inhibitory activity.

Meanwhile, (6) in the specification of GB1195628, the compound of theformula (B): ##STR5## wherein Ar^(B) is phenyl, phenyl substituted byone or more halogen, lower alkyl, lower alkoxy, NO₂, NH₂, CN or SCH₃ ;R^(B) is hydrogen, lower alkyl; R^(1B) is hydrogen, lower alkyl, benzyl;R^(2B) is CN, COOH, COO(lower alkyl), CONH2, CONH(lower alkyl),CON(lower alkyl)₂,

is disclosed to be useful as antiinflammatory. For example, the compoundof the formula: ##STR6## which is available in the market as anantiinflammatory agent (Tolmetin), is disclosed.

(7) In the specification of GB1327308, the compound of the formula (C):##STR7## wherein Ar₂ ^(C) is thienyl, 5-methylthienyl or substitutedphenyl; R^(3C) is COOH, COO(lower alkyl) etc.; R^(4C) is lower alkyl;R^(5C) is lower alkyl; R^(6C) is hydrogen, lower alkyl,

is disclosed to be useful as antiinflammatory. For example, the compoundof the formula: ##STR8## which is available in the market as ananalgesic, antiinflammatory agent (Zomepirac), is disclosed.

(8) In the specification of GB 1331505, the compound of the formula (D):##STR9## wherein R^(D) is hydrogen, C1-4 alkyl; R^(1D) is hydrogen, C1-4alkyl; R2D is hydrogen, lower alkyl etc.; Ar^(D) is phenyl, cyclohexyl,heterocyclic group,

is disclosed to be useful as antiinflammatory.

(9) In the specification of U.S. Pat. No. 3,801,605, the compound of theformula (E): ##STR10## wherein R^(E) is COOH, (C1-5 alkoxy)carbonyl, CN,CONH₂ ; Ar^(E) is phenyl, phenyl substituted by halogen, SCH₃, C1-5alkyl or alkoxy,

is disclosed to be useful as antiphlogistics.

(10) In the specification of GB1390866, the compound of the formula (F):##STR11## wherein R^(F) is hydrogen, lower alkyl; R^(1F) is hydrogen,methyl; R^(2F) is hydrogen, methyl; r^(3f) is --COOH, --COO(loweralkyl); R^(4F) is benzyl, cyclopentyl, cyclohexyl, is disclosed to beuseful as antiinflammatory. For example, the compounds of the formulae:##STR12## and ethyl ester thereof are disclosed.

(11) The compounds of the formulae: ##STR13## and methyl ester thereofare disclosed to be useful as antiinflammatory (Farmaco Ed. Sc., 41(4),281-289 (1986)).

(12) In the specification of DE4325204, published on Feb. 2, 1995, thecompound of the formula (G-I), (G-II), (G-III), (G-IV): ##STR14##wherein R^(1G) is --COOH or X^(G) --COOH in which X^(G) is C1-8alkyl,C2-8 alkenyl or alkynyl etc.; R^(3G) is --CO--CH₃, --CO--Y^(G) or--COY^(G) -Aryl in which Y^(G) is C2-19 alkyl, alkenyl or alkynyl etc.,R^(2G), R^(4G), R^(5G) is hydrogen, C1-20 alkyl, C2-20 alkenyl oralkynyl, Aryl, --Z^(G) -Aryl etc., in which Z^(G) is C1-20 alkyl, C2-10alkenyl or alkynyl etc; is disclosed to be useful as phospholipase A2inhibitors.

(13) In the specification of JP Kokai Hei 7-138227 published on May 30,1995, the compounds of the formula (H): ##STR15## wherein R^(1H) is (i)hydrogen, (ii) C1-3 saturated or unsaturated alkyl optionallysubstituted by OH, SH, halogen, COOH, alkoxy, alkoxycarbonyl oraryloxycarbonyl, (iii) COOH, alkoxycarbonyl, aryloxycarbonyl, (iv)benzoyl optionally substituted by halogen, (v) phenyl or tosyl, (vi)carbonyl group connected with alkoxycarbonylethyl; R^(2H) and R^(5H) is(i) hydrogen, (ii) methyl optionally substituted by OH, COOH,alkoxycarbonyl, (iii) --CHO, COOH, acethyl, propionyl, (iv) benzoyloptionally substituted by halogen (v) carbonyl group connected withalkoxycarbonylethyl, (vi) 3-alkoxycarbonyl-2-alkoxy-2-propenyl, (vii)nitrophenyl;

R^(3H) and R^(4H) is (i) hydrogen, (ii) aryloxycarbonyl, (iii) carbonylgroup connected with methyl or ethyl substituted by alkoxycarbonyl, (iv)benzoyl optionally substituted by halogen, is disclosed to be useful asgrowth of hair.

PURPOSE OF INVENTION

Energetic investigation have been carried out in order to discovercompounds of non-steroidal formula having 5α-reductase inhibitoryactivity, the present inventors have found that compounds of the formula(Ia) having 5α-reductase inhibitory activity and have accomplished thepresent invention.

COMPARISON WITH THE RELATED ARTS

The compounds disclosed in the related arts (1), (2), (3) and (5) arebenzoic acid derivatives, indole derivatives or indolizine derivatives.The compounds of the formula (Ia) of the present invention are pyrrole,thiophene, furan, imidazole, thiazole, oxazole and triazole derivatives.Therefore, the compounds of the present invention differ from thosecompounds.

In case of X^(A) is phenylene or naphthalene and A^(A) is thiophene, thecompound of the formula (A) in the specification of WO9313099 of therelated arts (4) is the compound of the following formula (Aa):##STR16## wherein the all symbols are the same meaning as hereinbeforedefined.

The compounds which Z is thiophene in the formula (Ia) of the presentinvention are following thiophene compounds. ##STR17## However, thosecompounds of the formula (Ie) in the present invention are notoverlapped with the above compounds of the formula (Aa). In thespecification of WO9313099, the following two thiophene compounds aredescribed. ##STR18##

The compounds in the related arts (6), (7), (8), (9), (10) and (11) aredisclosed to be useful as antiinflammatory. There are not descriptionthat the compound in the related arts (6), (7), (8), (9), (10) and (11)possess 5α-reductase inhibitory activity. It is not able to expect atall that the compounds having pyrrole ring, thiophene ring or furan ringpossess 5α-reductase inhibitory activity.

The compounds wherein Z is pyrrole included nitrogen substituted by R⁴ ;E is C1-6 alkylene; D is benzene; R¹ is hydrogen; R³ is R³⁻¹ ; R³⁻¹ ishydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio,trifluoromethyl; the other symbols are the same meaning as hereinbeforedefined; in the formula (Ia) of the present invention represents thefollowing compounds of the formula (If). ##STR19##

These compounds of the formula (If) are broadly overlapped with thecompounds wherein R^(3G) is --CO--Y^(G) -Aryl in the formula (G-I),(G-II) and (G-III) in the specification of DE-4325204 of the related art(12). However, in the specification of DE 4325204, the only one examplecompound wherein R^(3G) is --CO--Y^(G) -Aryl is disclosed, but is notincluded in the extent of the present invention. Moreover, the compoundsin the specification of DE4325204 are disclosed to be useful asphospholipase A2 inhibitors. There is no description that the compoundsin the specification of DE4325204 possess 5α-reductase inhibitoryactivity. The compounds of the present invention are not overlapped withthe compound of JP Kokai Hei 7-138227 of the related art (13).

DISCLOSURE OF THE INVENTION

The present invention is related to novel use of known compounds, novelcompounds, use of the novel compounds and process for the preparation ofthe novel compounds.

Accordingly, the present invention is related to 1) An inhibitory agenton 5α-reductase which comprises a compound of the formula (Ia):##STR20## wherein Z is pyrrole included nitrogen substituted by R⁴,thiophene, furan, imidazole included nitrogen substituted by R⁴,thiazole, oxazole, triazole included nitrogen substituted by R⁴, inwhich R⁴ is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl;

A is bond, C1-6 alkylene or C2-6 alkenylene;

E is bond or C1-6 alkylene;

D is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane,indene, cyclopenta(C4-7)cycloalkane, ##STR21## in which m is 0 or 1, orbenzene fused 4-7 membered heterocyclic ring containing one nitrogen,one sulfur or one oxygen atom;

R¹ is hydrogen or C1-4 alkyl;

R² is hydrogen or C1-4 alkyl;

n is 1-3;

R³ each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy,halogen, nitro, methylthio, trifluoromethyl or cyano,

(2) --Q--T--U--R⁵

in which Q is bond or C1-6 alkylene;

T is bond, --O--, ##STR22## --S--, --SO₂ --, --NR⁷ -- or --NR⁷ CO--, inwhich R⁷ is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl andnitrogen atom in --NR⁷ CO-- may be connected with --Q-- or --U--;

U is bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene or C1-6alkylene --O--, in which oxygen atom can be connected with R⁵ only;

R⁵ is (i) C4-7 cycloalkyl, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7membered heterocyclic ring containing one nitrogen, one sulfur or oneoxygen, or the benzene fused 4-7 membered heterocyclic ring containingone nitrogen, one sulfur or one oxygen,

or rings in (i), (ii), (iii), (iv) of R⁵ may be substituted by 1-3 ofC1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro orCOR⁶, in which R⁶ is C1-4 alkyl, NR⁸ R⁹, in which R⁸ and R⁹ each,independently, is hydrogen or C1-4 alkyl; or --Q--T--U--R⁵ is C7-10alkyl, C7-10 alkoxy;

or non-toxic salts thereof,

with the proviso that, the compounds wherein

(i) T is --O--, or --NR⁷ --, and U is bond and R⁵ is diphenylmethyl in--Q--T--U--R⁵ represented by R³, when Z is thiophene, E is bond and D isbenzene or napthalene,

(ii) T is --O--, or --NR⁷ --, and U is C1-6 alkylene and R⁵ is phenyl ordiphenylmethyl in --Q--T--U--R⁵ represented by R³, when Z is thiophene,E is bond and D is benzene or naphthalene,

(iii) Z is pyrrole included nitrogen substituted by R⁴, in which R⁴ ishydrogen, C1-3 alkyl or phenyl,

A is bond or methylene,

E is bond,

D is benzene,

R² is hydrogen or methyl and

R³ each, independently, is hydrogen or halogen, are excluded,

2) a compound of the formula (Ib): ##STR23## wherein Z is pyrroleincluded nitrogen substituted by R⁴, thiophene, furan, imidazoleincluded nitrogen substituted by R⁴, thiazole, oxazole, triazoleincluded nitrogen substituted by R⁴, in which R⁴ is hydrogen, C1-4alkyl, phenyl or phenyl(C1-4)alkyl;

A is bond, C1-6 alkylene or C2-6 alkenylene;

E is bond or C1-6 alkylene;

D is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane,indene, cyclopenta(C4-7)cycloalkane, ##STR24## in which m is 0 or 1, orbenzene fused 4-7 membered heterocyclic ring containing one nitrogen,one sulfur or one oxygen atom;

R¹ is hydrogen or C1-4 alkyl;

R² is hydrogen or C1-4 alkyl;

n is 1-3;

R³ each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy,halogen, nitro, methylthio, trifluoromethyl or cyano,

(2) --Q--T--U--R⁵

in which Q is bond or C1-6 alkylene;

T is bond, --O--, ##STR25## --S--, --SO₂ --, --NR⁷ -- or --NR⁷ CO--, inwhich R⁷ is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl andnitrogen atom in --NR⁷ CO-- may be connected with --Q-- or --U--;

U is bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene or C1-6alkylene --O--, in which oxygen atom can be connected with R⁵ only;

R⁵ is (i) C4-7 cycloalkyl, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7membered heterocyclic ring containing one nitrogen, one sulfur or oneoxygen, or the benzene fused 4-7 membered heterocyclic ring containingone nitrogen, one sulfur or one oxygen,

or rings in (i), (ii), (iii), (iv) of R⁵ may be substituted by 1-3 ofC1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro orCOR⁶, in which R⁶ is C1-4 alkyl, NR⁸ R⁹, in which R⁸ and R⁹ each,independently, is hydrogen or C1-4 alkyl;

or --Q--T--U--R⁵ is C7-10 alkyl, C7-10 alkoxy; or non-toxic saltsthereof, with the proviso that,

(a) compounds wherein

(i) T is --O--, or --NR⁷ --, and U is bond and R⁵ is diphenylmethyl in--Q--T--U--R⁵ represented by R³, when Z is thiophene, E is bond and D isbenzene or naphthalene,

(ii) T is --O--, or --NR⁷ --, and U is C1-6 alkylene and R⁵ is phenyl ordiphenylmethyl in --Q--T--U--R⁵ represented by R³, when Z is thiophene,E is bond and D is benzene or napthalene, are excluded;

(b) at least one R³ of (R³)_(n) is a substituent selected from group (2)that is --Q--T--U--R⁵, when E is bond and D is benzene;

(c) all R³ of (R³)_(n) are not hydrogen at the same time, when E is bondand D is C4-7 cycloalkane, or E is methylene and D is benzene;

(d) 2- 5- 2-chloro-4-(1H-pyrrol-1-yl)benzoyl!thiophen-2-yl!acetic acidand methyl ester thereof and

2- 5-2-chloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)benzoyl!thiophen-2-yl!aceticmethyl ester thereof are excluded.

3) process for the preparation of a compound of the formula (Ib) andnon-toxic salts thereof.

In the present invention, C4-7 cycloalkane of the following formula:

    D

means cyclobutane, cyclopentane, cyclohexane, cycloheptane.

In the present invention, benzo(C4-7)cycloalkane of the followingformula:

    D

means benzocyclobutane, 2,3-dihydroindene,1,2,3,4-tetrahydronaphthalene, 1,2,3,4,5-pentahydrobenzocycloheptene.

In the present invention, cyclopenta(C4-7)cycloalkane of the followingformula:

    D

means cyclopentacyclobutane, cyclopentacyclopentane,cyclopentacyclohexane, cyclopentacycloheptane.

In the present invention, ##STR26## of the following formula:

    D

means ##STR27##

In the present invention, C1-6 alkylene represented by A, E, Q or U andincluded in C1-6 alkylene --O-- represented by U, means methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethyleneand isomeric groups thereof.

C2-6 alkenylene represented by A or U mean vinylene, propenylene,butenylene, pentenylene, hexenylene and isomeric groups thereof.

C2-6 alkynylene represented by U means ethynylene, propynylene,butenylene, pentenylene, hexenylene and isomeric groups thereof.

C1-4 alkyl represented by R¹, R², R⁴, R⁶, R⁷, R⁸ or R⁹ mean methyl,ethyl, propyl, butyl and isomeric groups thereof.

C1-6 alkyl represented by R³ means methyl, ethyl, propyl, butyl, pentyl,hexyl and isomeric groups thereof.

C1-6 alkoxy represented by R³ means methoxy, ethoxy, propoxy, butoxy,pentyloxy, hexyloxy and isomeric groups thereof.

Halogen represented by R³ means fluorine, chlorine, bromine and iodine.

Phenyl(C1-4)alkyl represented by R⁴ or R⁷ means methyl, ethyl, propyl,butyl and isomeric groups thereof substituted by 1 of phenyl.

C4-7 cycloalkyl represented by R⁵ means cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

4-7 membered heterocyclic ring containing one nitrogen represented by R⁵means, for example, pyrrole, pyridine, azepine and partially or fullysaturated ring thereof.

Benzene fused 4-7 membered heterocyclic ring containing one nitrogenrepresented by R⁵ or D means, for example, indole, isoindole, quinoline,isoquinoline, benzoazepine and partially or fully saturated ring thereof(e.g. indoline, isoindoline).

4-7 membered heterocyclic ring containing one sulfur represented by R⁵means, for example, thiophene, thiain, thiepin and partially or fullysaturated ring thereof.

Benzene fused 4-7 membered heterocyclic ring containing one sulfurrepresented by R⁵ or D means, for example, benzothiophene, benzothiain,benzothiepin and partially or fully saturated ring thereof.

4-7 membered heterocyclic ring containing one oxygen represented by R⁵means, for example, furan, pyran, oxepin and partially or fullysaturated ring thereof.

Benzene fused 4-7 membered heterocyclic ring containing one oxygenrepresented by R⁵ or D means, for example, benzofuran, benzopyran,benzoxepine and partially or fully saturated ring thereof (e.g. chroman,isochroman).

C1-10 alkyl as substituents of rings in groups represented by R⁵ meansmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyland isomeric groups thereof.

C1-10 alkoxy as substituents of rings in groups represented by R⁵ meansmethoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy, nonyloxy, decyloxy and isomeric groups thereof.

Halogen as substituents of rings in groups represented by R⁵ meansfluorine, chlorine, bromine and iodine.

C7-10 alkyl represented by --Q--T--U--R⁵ means heptyl, octyl, nonyl,decyl and isomeric groups thereof.

C7-10 alkoxy represented by --Q--T--U--R⁵ means heptyloxy, octyloxy,nonyloxy, decyloxy and isomeric groups thereof.

Preferable Compounds

In the compound of the present invention of the formula (Ia), thecompounds of the following formula (Ia-A), (Ia-B), (Ia-C), (Ia-D),(Ia-E), (Ia-F), (Ia-G) and non-toxic salts thereof are preferable.##STR28## wherein all the symbols are the same meaning as hereinbeforedefined.

And the compounds of the following formula (Ia-H), (Ia-I), (Ia-J) andnon-toxic salts thereof are preferable. ##STR29## wherein all thesymbols are the same meaning as hereinbefore defined.

More specifically, the compounds of the following formula (Ia-1),(Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-9), (Ia-10),(Ia-11), (Ia-12) and non-toxic salts thereof are preferable. ##STR30##wherein all the symbols are the same meaning as hereinbefore defined.

Especially preferable compounds are the compounds described in Exampleand the following compounds and non-toxic salts thereof.

    __________________________________________________________________________     ##STR31##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) diphenylmethyl   (2) di(4-propylphenyl)methyl    (3) 3-pyridinyl      (4) 2-furanyl    (5) cyclohexylmethyl (6) 4-ethylbenzyl    (7) 4-methoxybenzyl  (8) 2,2-diphenylethyl    (9) 2,2-di(4-propylphenyl)ethyl                         (10) diphenylmethyloxy    (11) di(4-propylphenyl)methyloxy                         (12) 3-pyridinyloxy    (13) cyclohexylamino (14) phenylamino    (15) diphenylmethylamino                         (16) di(4-propylphenyl)methylamino    (17) 3-pyridinylamino                         (18) 1-phenylethyloxy    (19) 2,2-diphenylethyloxy                         (20) 2,2-di(4-propylphenyl)ethyloxy    (21) 3-pyridinylmethyloxy                         (22) 2-thienylmethyloxy    (23) 2-furanylmethyloxy                         (24) cyclohexylcarbonyl    (25) do(4-propylphenyl)methylcarbobyl                         (26) 3-pyridinylcarbonyl    (27) 2-thienylcarbonyl                         (28) 2-furanylcarbonyl    (29) cyclohexylmethyloxymethyl                         (30) benzyloxymethyl    (31) 2,2-di(4-propylphenyl)ethyloxymethyl                         (32) cyclohexylmethylaminomethyl    (33) benzylaminomethyl                         (34) 2,2-di(4-propylphenyl)ethylaminomethyl    (35) cyclohexylmethylcarbonylmethyl                         (36) benzylcarbonylmethyl    (37) 2,2-di(4-propylphenyl)ethylcarbonylmethyl                         (38) diphenylamino    (39) dibenzylamino   (40) benzylamino    (41) 4-ethylbenzylamino                         (42) 1-phenylethylamino    (43) 2,2-diphenylethylamino                         (44) 2,2-di(4-propylphenyl)ethylamino    (45) 3-pyridinylmethylamino                         (46) 2-thienylmethylamino    (47) 2-furanylmethylamino                         (48) 2-cyclohexylethyl    (49) 2-cyclohexylethenyl                         (50) 2-cyclohexylethynyl    (51) 4-methoxycyclohexyl                         (52) 4-fluorocyclohexyl    (53) 3-nitrocyclohexyl                         (54) 4-trifluoromethylphenyl    (55) cyclohexyl      (56) phenylthio    (57) diphenylmethylthio                         (58) phenylthiomethyl    (59) diphenylmethylthiomethyl                         (60) cyclohexylulfonyl    (61) phenylsulfonyl  (62) diphenylsulfonyl    (63) cyclohexylsulfonylmethyl                         (64) diphenylsulfonylmethyl    (65) heptyl    __________________________________________________________________________     ##STR32##    R.sup.0              R.sup.0    __________________________________________________________________________    (1) 5-indenyl        (2) 1,2,3,4-tetrahydronaphthalen-2-yl    (3) 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propyl                         (4) 4,5,6,7-tetrahydroinden-5-yl    (5) 2,3-dimethyl-4-benzyloxyphenyl                         (6) 2,3-dimethyl-4-(1-phenylethyloxy)phenyl    (7) cyclopentyl      (8) cycloheptyl    (9) 4-phenylcyclopentyl                         (10) 4-phenylcycloheptyl    (11) 2-chloro-4-pyrrolylphenyl                         (12) 2-chloro-4-(2,5-dimethylpyrrolyl)phenyl    __________________________________________________________________________     ##STR33##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) 4-ethylphenyl    (3) 4-methoxyphenyl  (4) pyrrolyl    (5) 3-pyridinyl      (6) 2-thienyl    (7) 2-furanyl        (8) benzyl    (9) phenyloxy        (10) benzyloxy    (11) benzoyl         (12) phenylamino    (13) benzylamino     (14) diphenylamino    (15) phenylcarbonylamino                         (16) phenylthiomethyl    (17) phenylsulfonylmethyl                         (18) 2-cyclohexylmethyl    (19) 2-phenylethyl   (20) 2-cyclohexylethenyl    (21) 2-phenylethenyl (22) 2-cyclohexylethenyl    (23) 2-phenylethynyl (24) 4-fluorophenyl    (25) 3-nitrophenyl   (26) 4-trifluoromethylphenyl    (27) 5-bromo-2-thienyl                         (28) 2-isoindolinyl    (29) benzothiophen-2-yl                         (30) heptyl    (31) hydrogen        (32) 1,2,3,4-tetrahydronaphthalen-2-yl    (33) ethyl           (34) methoxy    (35) nitro           (36) fluoro    (37) trifluoromethyl    __________________________________________________________________________     ##STR34##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) 4-ethylphenyl    (3) 4-methoxyphenyl  (4) diphenylmethyl    (5) di(4-propylphenyl)methyl                         (6) 3-pyridinyl    (7) 2-thienyl        (8) 2-furanyl    (9) cyclohexylmethyl (10) benzyl    (11) 4-ethylbenzyl   (12) 4-methoxybenzyl    (13) 2,2-diphenylethyl                         (14) 2,2-di(4-propylphenyl)ethyl    (15) cyclohexyl      (16) 3-pyridinyloxy    (17) cyclohexylaino  (18) phenylamino    (19) 3-pyridinylamino                         (20) 3-pyridinylmethyloxy    (21) 2-thienylmethyloxy                         (22) 2-furanylmethyloxy    (23) cyclohexylcarbonyl                         (24) benzoyl    (25) di(4-propylphenyl)methylcarbonyl                         (26) 3-pyridinylcarbonyl    (27) 2-thienylcarbonyl                         (28) 2-furanylcarbonyl    (29) cyclohexylmethyloxymethyl                         (30) cyclohexylmethylaminomethyl    (31) cyclohexylmethylcarbonylmethyl                         (32) benzylcarbonylmethyl    (33) 2,2-di(4-propylphenyl)ethylcarbonylmethyl                         (34) diphenylamino    (35) 3-pyridinylmethylamino                         (36) pyrrolyl    (37) 3-pyridinylmethylamino                         (38) 2-thienylmethylamino    (39) 2-furanylmethylthio                         (40) 2-cyclohexylethyl    (41) 2-phenylethyl   (42) 2-cyclohexylethenyl    (43) 2-phenylethenyl (44) 2-cyclohexylethynyl    (45) 2-phenylethynyl (46) 4-fluorophenyl    (47) 3-nitrophenyl   (48) 4-trifluoromethylphenyl    (49) cyclohexylthiomethyl                         (50) phenylthiomethyl    (51) diphenylmethylthiomethyl                         (52) cyclohexylsulfonylmethyl    (53) phenylsulfonylmethyl                         (54) dipenylsulfonylmetyl    (55) 5-bromo-2-thienyl                         (56) 2-isoindolinyl    (57) benzothiophen-2-yl                         (58) heptyl    __________________________________________________________________________     ##STR35##    R.sup.0              R.sup.0    __________________________________________________________________________    (1) 2-naphthyl       (2) 5-indenyl    (3) 9-oxofluoren-2-yl                         (4) 1,2,3,4-tetrahydronaphthalen-2-yl    (5) 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propyl                         (6) 4,5,6,7-tetrahydroinden-5-yl    (7) 2-methyl-4-benzyloxyphenyl                         (8) 2,3-dimethyl-4-benzyloxyphenyl    (9) 2,3-dimethyl-4-(1-phenylethyloxy)phenyl                         (10) cyclopentyl    (11) cycloheptyl     (12) 4-phenylcyclopentyl    (13) 4-phenylcycloheptyl                         (14) 2-chloro-4-pyrrolylphenyl    (15) 2-chloro-4-(2,5-dimethylpyrrolyl)phenyl    __________________________________________________________________________     ##STR36##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) phenyl    (3) 4-ethylphenyl    (4) 4-methoxyphenyl    (5) pyrrolyl         (6) 3-pyridinyl    (7) 2-thienyl        (8) 2-furanyl    (9) benzyl           (10) phenyloxy    (11) benzyloxy       (12) benzoyl    (13) phenylamino     (14) benzylamino    (15) diphenylamino   (16) phenylcarbonylamino    (17) phenylthiomethyl                         (18) phenylsulfonylmethyl    (19) 2-cyclohexylethyl                         (20) 2-phenylethyl    (21) 2-cyclohexylethenyl                         (22) 2-enylethenyl    (23) 2-cyclohexylethynyl                         (24) 2-phenylethynyl    (25) 4-fluorophenyl  (26) 3-nitrophenyl    (27) 4-trifluoromethylphenyl                         (28) 5-bromo-2-thienyl    (29) 2-isoindolinyl  (30) benzothiophen-2-yl    (31) heptyl          (32) hydrogen    (33) 1,2,3,4-tetrahydronaphthalen-2-yl                         (34) i-butyl    (35) ethyl           (36) methoxy    (37) nitro           (38) fluoro    (39) trifluoromethyl    __________________________________________________________________________     ##STR37##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) 4-ethylphenyl    (3) 4-methoxyphenyl  (4) diphenylmethyl    (5) di(4-propylphenyl)methyl                         (6) 3-pyridinyl    (7) 2-thienyl        (8) 2-furanyl    (9) cyclohexylmethyl (10) benzyl    (11) 4-ethylbenyl    (12) 4-methoxyphenyl    (13) 2,2-diphenylethyl                         (14) 2,2-di(4-propylphenyl)ethyl    (15) cyclohexyloxy   (16) phenyloxy    (17) diphenylmethyloxy                         (18) di(4-propylphenyl)methyl    (19) 3-pyridinyloxy  (20) cyclohexylamino    (21) phenylamino     (22) diphenylmethylamino    (23) di(4-propylphenyl)methylamino                         (24) 3-pyridinylamino    (25) benzyloxy       (26) 4-ethylbenzyloxy    (27) 1-phenylethyloxy                         (28) 2,2-diphenylethyloxy    (29) 2,2-di(4-propylphenyl)ethyloxy                         (30) 3-pyridinylmethyloxy    (31) 2-thienylmethyloxy                         (32) 2-furanylmethyloxy    (33) cyclohexylcarbonyl                         (34) benzoyl    (35) di(4-propylphenyl)methylcarbonyl                         (36) 3-pyridinylcarbonyl    (37) 2-thienylcarbonyl                         (38) 2-furanylcarbonyl    (39) cyclohexylmethyloxymethyl                         (40) benzyloxymethyl    (41) 2,2-di(4-propylphenyl)ethyloxymethyl                         (42) cyclohexylmethylaminomethyl    (43) benzylaminomethyl                         (44) 2,2-di(4-propylphenyl)ethylaminomethyl    (45) cyclohexylmethylcarbonylmethyl                         (46) benzylcarbonylmethyl    (47) 2,2-di(4-propylphenyl)ethylcarbonylmethyl                         (48) diphenylamino    (49) dibenzylamino   (50) phenylcarbonylamino    (51) pyrrolyl        (52) benzylamino    (53) 4-ethylbenzylamino                         (54) 1-phenylethylamino    (55) 2,2-diphenylethylamino                         (56) 2,2-di(4-propylphenyl)ethylamino    (57) 3-pyridinylmethylamino                         (58) 2-thienylmethylamino    (59) 2-furanylmethylamino                         (60) 2-cyclohexylethyl    (61) 2-phenylethyl   (62) 2-cyclohexylethenyl    (63) 2-phenylethenyl (64) 2-cyclohexylethynyl    (65) 2-phenylethynyl (66) 4-fluorophenyl    (67) 3-nitrophenyl   (68) 4-trifluoromethylphenyl    (69) cyclohexylthiomethyl                         (70) phenylthiomethyl    (71) diphenylmethylthiomethyl                         (72) cyclohexylsulfonylmethyl    (73) phenylsulfonylmethyl                         (74) diphenylsulfonylmethyl    (75) 5-bromo-2-thienyl                         (76) 2-isoindolinyl    (77) benzothiophen-2-yl                         (78) heptyl    __________________________________________________________________________     ##STR38##    R.sup.0              R.sup.0    __________________________________________________________________________    (1) 2-naphthyl       (2) 5-indenyl    (3) 9-oxofluoren-2-yl                         (4) 1,2,3,4-tetrahydronaphthalen-2-yl    (5) 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propyl                         (6) 4,5,6,7-tetrahydroinden-5-yl    (7) 2-methyl-4-benzyloxyphenyl                         (8) 2,3-demethyl-4-benzyloxyphenyl    (9) 2,3-dimethyl-4-(1-phenylethyloxy)phenyl                         (10) cyclopentyl    (11) cycloheptyl     (12) 4-phenylcyclopentyl    (13) 4-phenylcycloheptyl                         (14) 2-chloro-4-pyrrolyphenyl    (15) 2-chloro-4-(2,5-dimethylpyrrolyl)phenyl    __________________________________________________________________________     ##STR39##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) phenyl    (3) 4-ethylphenyl    (4) 4-methoxyphenyl    (5) pyrrolyl         (6) 3-pyridinyl    (7) 2-thienyl        (8) 2-furanyl    (9) benzyl           (10) phenyloxy    (11) benzyloxy       (12) benzoyl    (13) phenylamino     (14) benzylamino    (15) diphenylamino   (16) phenylcarbonylamino    (17) phenylthiomethyl                         (18) phenylsulfonylmethyl    (19) 2-cyclohexylethyl                         (20) 2-phenylethyl    (21) 2-cyclohexylethenyl                         (22) 2-phenylethenyl    (23) 2-cyclohexylethynyl                         (24) 2-phenylethynyl    (25) 4-fluorophenyl  (26) 3-nitrophenyl    (27) 4-trifluoromethylphenyl                         (28) 5-bromo-2-thienyl    (29) 2-isoindolinyl  (30) benzothiophen-2-yl    (31) heptyl          (32) hydrogen    (33) 1,2,3,4-tetrahydronaphthalen-2-yl                         (34) t-butyl    (35) ethyl           (36) methoxy    (37) nitro           (38) fluoro    (39) trifluoromethyl    __________________________________________________________________________     ##STR40##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) 4-ethylphenyl    (3) 4-methoxyphenyl  (4) diphenylmethyl    (5) di(4-propylphenyl)methyl                         (6) 3-pyridinyl    (7) 2-thienyl        (8) 2-furanyl    (9) cyclohexylmethyl (10) benzyl    (11) 4-ethylbenzyl   (12) 4-methoxybenzyl    (13) 2,2-diphenylethyl                         (14) 2,2-di(4-propylphenyl)ethyl    (15) cyclohexyloxy   (16) phenyloxy    (17) diphenylmethyloxy                         (18) di(4-propylphenyl)methyloxy    (19) 3-pyridinyloxy  (20) cyclohexylamino)    (21) phenylamino     (22) diphenylmethylamino    (23) di(4-propylphenyl)methylamino                         (24) 3-pyridinylamino    (25) benzyloxy       (26) 4-ethylbenzyloxy    (27) 1-phenylethyloxy                         (28) 2,2-diphenylethyloxy    (29) 2,2-di(4-propylphenyl)ethyloxy                         (30) 3-pyridinylmethyloxy    (31) 2-thienylmethyloxy                         (32) 2-furanylmethyloxy    (33) cyclohexylcarbonyl                         (34) benzoyl    (35) di(4-propylphenyl)methylcarbonyl                         (36) 3-pyridinylcarbonyl    (37) 2-thienylcarbonyl                         (38) 2-furanylcarbonyl    (39) cyclohexylmethyloxymethyl                         (40) benzyloxymethyl    (41) 2,2-di(4-propylphenyl)ethyloxymethyl                         (42) cyclohexylmethylaminomethyl    (43) benzylaminomethyl                         (44) 2,2-di(4-propylphenyl)ethylaminomethyl    (45) cyclohexylmethylcarbonylmethyl                         (46) benzylcarbonylmethyl    (47) 2,2-di(4-propylphenyl)ethylcarbonlmethyl                         (48) diphenylamino    (49) dibenzylamino   (50) phenylcarbonylamino    (51) pyrrolyl        (52) benzylamino    (53) 4-ethylbenzylamino                         (54) 1-phenylethylamino    (55) 2,2-diphenylethylamino                         (56) 2,2-di(4-propylphenyl)ethylamino    (57) 3-pyrindinylmethylamino                         (58) 2-thienylmethylamino    (59) 2-furanylmethylamino                         (60) 2-cyclohexylethyl    (61) 2-phenylethyl   (62) 2-cyclohexylethenyl    (63) 2-phenylethenyl (64) 2-cyclohexylethynyl    (65) 2-phenylethynyl (66) 4-fluorophenyl    (67) 3-nitrophenyl   (68) 4-trifluoromethylphenyl    (69) cyclohexylthiomethyl                         (70) phenylthiomethyl    (71) diphenylmethylthiomethyl                         (72) cyclohexylsullfonylmethyl    (73) phenylsulfonylmethyl                         (74) diphenylsulfonylmethyl    (75) 5-bromo-2-thienyl                         (76) 2-isoindolinyl    (77) benzothiophen-2-yl                         (78) heptyl    __________________________________________________________________________     ##STR41##    R.sup.0              R.sup.0    __________________________________________________________________________    (1) 2-naphthyl       (2) 5-indenyl    (3) 9-oxofluoren-2-yl                         (4) 1,2,3,4-tetrahydronaphthalen-2-yl    (5) 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propyl                         (6) 4,5,6,7-tetrahydroinden-5-yl    (7) 2-methyl-4-benzyloxyphenyl                         (8) 2,3-dimethyl-4-benzyloxyphenyl    (9) 2,3-dimethyl-4-(1-phenylethyloxy)phenyl                         (10) cyclopentyl    (11) cycloheptyl     (12) 4-phenylcyclopentyl    (13) 4-phenylcycloheptyl                         (14) 2-chloro-4-pyrrolylphenyl    (15) 2-chloro-4-(2,5-dimethylpyrrolyl)phenyl    __________________________________________________________________________     ##STR42##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) phenyl    (3) 4-ethylphenyl    (4) 4-methoxyphenyl    (5) pyrrolyl         (6) 3-pyridinyl    (7) 2-thienyl        (8) 2-furanyl    (9) benzyl           (10) phenyloxy    (11) benzyloxy       (12) benzoyl    (13) phenylamino     (14) benzylamino    (15) diphenylamino   (16) phenylcarbonylamino    (17) phenylthiomethyl                         (18) phenylsulfonylmethyl    (19) 2-cyclohexylethyl                         (20) 2-phenylethyl    (21) 2-cyclohexylethenyl                         (22) 2-phenylethenyl    (23) 2-cyclohexylethynyl                         (24) 2-phenylethynyl    (25) 4-fluorophenyl  (26) 3-nitrophenyl    (27) 4-trifluoromethylphenyl                         (28) 5-bromo-2-thienyl    (29) 2-isoindolinyl  (30) benzothiophen-2-yl    (31) heptyl          (32) hydrogen    (33) 1,2,3,4-tetrahydronaphthalen-2-yl                         (34) t-butyl    (35) ethyl           (36) methoxy    (37) nitro           (38) fluoro    (39) trifluoromethyl    __________________________________________________________________________     ##STR43##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) 4-ethylphenyl    (3) 4-methoxyphenyl  (4) diphenylmethyl    (5) di(4-propylphenyl)methyl                         (6) 3-pyridinyl    (7) 2-thienyl        (8) 2-furanyl    (9) cyclohexylmethyl (10) benzyl    (11) 4-ethylbenzyl   (12) 4-methoxybenzyl    (13) 2,2-diphenylethyl                         (14) 2,2-di(4-propylphenyl)ethyl    (15) cyclohexyloxy   (16) phenyloxy    (17) diphenylmethyloxy                         (18) di(4-propylphenyl)methyloxy    (19) 3-pyridinyloxy  (20) cyclohexylamino    (21) phenylamino     (22) diphenylmethylamino    (23) di(4-propylphenyl)methylamino                         (24) 3-pyridinylamino    (25) benzyloxy       (26) 4-ethylbenzyloxy    (27) 1-phenylethyloxy                         (28) 2,2-diphenylethyloxy    (29) 2,2-di(4-propylphenyl)ethyloxy                         (30) 3-pyridinylmethyloxy    (31) 2-thienylmethyloxy                         (32) 2-furanylmethyloxy    (33) cyclohexylcarbonyl                         (34) benzoyl    (35) di(4-propylphenyl)methylcarbonyl                         (36) 3-pyridinylcarbonyl    (37) 2-thienylcarbonyl                         (38) 2-furanylcarbonyl    (39) cyclohexylmethyloxymethyl                         (40) benzyloxymethyl    (41) 2,2-di(4-propylphenyl)ethyloxymethyl                         (42) cyclohexylmethylaminomethyl    (43) benzylaminomethyl                         (44) 2,2-di(4-propylphenyl)ethylaminomethyl    (45) cyclohexylmethylcarbonylmethyl                         (46) benzylcarbonylmethyl    (47) 2,2-di(4-propylphenyl)ethylcarbonylmethyl                         (48) diphenylamino    (49) dibenzylamino   (50) phenylcarbonylamino    (51) pyrrolyl        (52) benzylamino    (53) 4-ethylbenzylamino                         (54) 1-phenylethylamino    (55) 2,2-diphenylethylamino                         (56) 2,2-di(4-propylphenyl)ethylamino    (57) 3-pyrdidinylmethylamino                         (58) 2-thienylmethylamino    (59) 2-furanylmethylamino                         (60) hydrogen    (61) 2-cyclohexylethyl                         (62) 2-phenylethyl    (63) 2-cyclohexylethenyl                         (64) 2-phenylethenyl    (65) 2-cyclohexylethynyl                         (66) 2-phenylethynyl    (67) 4-fluorophenyl  (68) 3-nitrophenyl    (69) 4-trifluoromethylphenyl                         (70) cyclohexylthiomethyl    (71) phenylthiomethyl                         (72) diphenylmethylthiomethyl    (73) cyclohexylsulfonylmethyl                         (74) phenylsulfonylmethyl    (75) diphenylsulfonylmethyl                         (76) 5-bromo-2-thienyl    (77) 2-isoindolinyl  (78) benzothiophen-2-yl    (79) heptyl    __________________________________________________________________________     ##STR44##    R.sup.0              R.sup.0    __________________________________________________________________________    (1) 2-naphthyl       (2) 5-indenyl    (3) 9-oxofluoren-2-yl                         (4) 1,2,3,4-tetrahydronaphthalen-2-yl    (5) 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propyl                         (6) 4,5,6,7-tetrahydroinden-5-yl    (7) 2-methyl-4-benzyloxyphenyl                         (8) 2,3-dimethyl-4-benzyloxyphenyl    (9) 2,3-dimethyl-4-(1-phenylethyloxy)phenyl                         (10) cyclopentyl    (11) cycloheptyl     (12) 4-phenylcyclopentyl    (13) 4-phenylcycloheptyl                         (14) 2-chloro-4-pyrrolylphenyl    (15) 2-chloro-4-(2,5-dimethylpyrrolyl)phenyl    __________________________________________________________________________     ##STR45##    R.sup.3              R.sup.3    __________________________________________________________________________    (1) cyclohexyl       (2) phenyl    (3) 4-ethylphenyl    (4) 4-methoxyphenyl    (5) pyrrolyl         (6) 3-pyridinyl    (7) 2-thienyl        (8) 2-furanyl    (9) benzyl           (10) phenyloxy    (11) benzyloxy       (12) benzoyl    (13) phenylamino     (14) benzylamino    (15) diphenylamino   (16) phenylcarbonylamino    (17) phenylthiomethyl                         (18) phenylsulfonylmethyl    (19) 2-cyclohexylethyl                         (20) 2-phenylethyl    (21) 2-cyclohexylethenyl                         (22) 2-phenylethenyl    (23) 2-cyclohexylethynyl                         (24) 2-phenylethynyl    (25) 4-fluorophenyl  (26) 3-nitrophenyl    (27) 4-trifluoromethylphenyl                         (28) 5-bromo-2-thienyl    (29) 2-isoindolinyl  (30) benzothiophen-2-yl    (31) heptyl          (32) hydrogen    (33) 1,2,3,4-tetrahydronaphthalen-2-yl                         (34) t-butyl    (35) ethyl           (36) methoxy    (37) nitro           (38) fluoro    (39) trifluoromethyl    __________________________________________________________________________     ##STR46##    No.  R.sup.2                (R.sup.3).sub.n                         No.  R.sup.2                                     (R.sup.3).sub.n    __________________________________________________________________________    (1)  hydrogen                4-methyl (2)  hydrogen                                     4-t-butyl    (3)  hydrogen                4-chloro (4)  hydrogen                                     4-methoxy    (5)  hydrogen                4-nitro  (6)  hydrogen                                     4-methylthio    (7)  hydrogen                4-trifluoromethyl                         (8)  hydrogen                                     4-cyano    (9)  hydrogen                4-fluoro (10) hydrogen                                     3,5-di-t-butyl    (11) methyl 4-t-butyl                         (12) methyl 4-chloro    (13) methyl 4-methyl (14) methyl 3,5-di-t-butyl    (15) hydrogen                4-isobutyl                         (16) hydrogen                                     4-bromo    (17) hydrogen                4-iodo   (18) hydrogen                                     4-hexyloxy    (19) hydrogen                4-isopropyloxy    __________________________________________________________________________     ##STR47##    No.  R.sup.2                (R.sup.3).sub.n                         No.  R.sup.2                                     (R.sup.3).sub.n    __________________________________________________________________________    (1)  hydrogen                4-methyl (2)  hydrogen                                     4-t-butyl    (3)  hydrogen                4-chloro (4)  hydrogen                                     4-methoxy    (5)  hydrogen                4-nitro  (6)  hydrogen                                     4-methylthio    (7)  hydrogen                4-trifluoromethyl                         (8)  hydrogen                                     4-cyano    (9)  hydrogen                4-fluoro (10) hydrogen                                     3,5-di-t-butyl    (11) methyl 4-t-butyl                         (12) methyl 4-chloro    (13) methyl 4-methyl (14) methyl 3,5-di-t-butyl    (15) hydrogen                4-isobutyl                         (16) hydrogen                                     4-bromo    (17) hydrogen                4-iodo   (18) hydrogen                                     4-hexyloxy    __________________________________________________________________________

In the present invention, it is able to formulate using each activeingredient or combination of more than two active ingredients.

Unless otherwise specified, all isomers are included in the invention.For example, alkyl, alkoxy, alkenylene and alkylene includes straightand branched ones. Double bond in alkenylene includes E, Z and EZmixture. Isomers generated by asymmetric carbon(s) e.g. branched alkylare included in the present invention.

Salts

The compounds of the formula (Ia) and (Ib) of the present invention maybe converted into the corresponding salts. Non-toxic and water-solublesalts are preferable. Suitable salts, for example, are as follows:

salts of alkaline metal (sodium, potassium etc.), salts of alkalineearth metal (calcium, magnesium etc.), ammonium salts, salts ofpharmaceutically acceptable organic amine (tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,N-methyl-D-glucamine etc.).

The compounds of the formula (Ia) and (Ib) may be converted into thecorresponding acid addition salts. Non-toxic and water-soluble salts arepreferable. Suitable salts, for example, are as follows: salts ofinorganic acids e. g. hydrochloride, hydrobromide, hydroiodide, sulfate,phosphate, nitrate; salts of organic acids e. g. acetate, lactate,tartarate, benzoate, citrate, methanesulphonate, ethanesulphonate,benzenesulphonate, toluenesulphonate, isedthioate, glucuronate,gluconate.

Process for the preparation

A compound of the formula (Ic): ##STR48## wherein all the symbols arethe same meaning as hereinbefore defined, in a compound of the presentinvention of the formula (Ia), may be prepared:

(1) by hydrolyzing an ester of the formula (Id): ##STR49## whereinR^(1a) is C1-4 alkyl and the other symbols are the same meaning ashereinbefore defined, or

(2) by hydrolyzing a compound of the formula (II): ##STR50## wherein allthe symbols are the same meaning as hereinbefore defined.

The compound of the formula (Id) among the compounds of the presentinvention, may be prepared:

(3) by reacting a compound of the formula (III): ##STR51## wherein X ishalogen, the other symbols are the same meaning as hereinbefore defined,

with a compound of the formula (IV) ##STR52## wherein all the symbolsare the same meaning as hereinbefore defined.

Compounds of the formula (Ia) wherein R⁴ is hydrogen and /or R⁷ ishydrogen, may be prepared:

(i) by using a compound of the formula (III) and (IV) wherein hydrogenrepresented by R⁴ and R⁷ is replaced by benzyloxycarbonyl (protectinggroup) as a staring material,

(ii) by reacting above compounds,

(iii) by hydrolyzing a compound obtained in above reaction (ii) using anacid (hydrochloric acid, trifluoroacetic acid etc.),

(iv) by hydrolyzing a compound obtained in above reaction (iii) using anaqueous solution of an alkaline (potassium hydroxide, sodium hydroxide,potassium carbonate, sodium carbonate etc.).

The reaction (1) is known, for example, it may be carried out in watermiscible organic solvent (methanol, ethanol, isopropanol,tetrahydrofuran(THF), dioxane or two or more of the mixture, etc.),using an aqueous solution of an alkaline (potassium hydroxide, sodiumhydroxide, potassium carbonate, sodium carbonate etc.) at -10°˜50° C.

The reaction (2) is known, for example, it may be carried out in watermiscible organic solvent (methanol, ethanol, isopropanol,tetrahydrofuran(THF), dioxane or two or more of the mixture, etc.),using an aqueous solution of an alkaline (potassium hydroxide, sodiumhydroxide, potassium carbonate, sodium carbonate etc.) at 40°˜150° C.

The reaction (3) is known, for example, it may be carried out in organicsolvent (xylene, chloroform, methylene chloride, THF, toluene,acetonitrile etc.), in the presence or absence of Lewis acid (aluminumchloride, iron(III) chloride, boron trifluoride diethyl etherate etc.)or an base (triethylamine, pyridine etc.) at 20°˜150° C.

Starting materials and reagents

The starting materials and reagents in the present invention are knownper se or may be prepared by known methods.

For example, a compound of the formula (II) may be prepared by using areaction depicted in following scheme: ##STR53## wherein all the symbolsare the same meaning as hereinbefore defined.

For example, a compound included in the formula (III) of the formula:##STR54## is on the market.

For example, a compound included in the formula (IV) of the formula:##STR55## is on the market.

For example, a compound included in the formula (V) of the formula:##STR56## is on the market. Pharmacological Activities

A compound of the formula (Ia) of the present invention possess aninhibitory activity on 5α-reductase and therefore are useful forprevention and/or treatment of diseases induced by the excess generationof dihydrotestosterone in mammals, especially human. The diseases suchas above, for example, are alopecia (e.g. androgenic alopecia), acnes,hypertrophy of prostate and prostatic cancer. An inhibitory activity on5α-reductase of the present invention is confirmed by the screeningsystem described hereafter

(1) Preparation of 5α-reductase from human prostates

Frozen human prostates were thawed on ice and minced with scissors intosmall pieces (˜1 mm³). The minced tissue was homogenized in 3 tissuevolumes of ice cold medium A (20 mM potassium phosphate, pH 6.5,containing 0.32M sucrose, 1 mM dithiothreitol, 50 μM NADPH, 1 mM EDTA),first with a Brinkmann Polytron and then with a Dounce homogenizer. Thehomogenate was filtered through gauze and the filtrate was centrifugedat 140,000×g at 4° C. for 60 min. The resulting pellet was washed with 3tissue volumes of medium A. The washed pellet was suspended (5-10 mgprotein/ml) in 20 mM potassium phosphate, pH 6.5, containing 20%glycerol, 50 μM NADPH and 1 mM dithiothreitol. An appropriate aliquot ofthis suspension was used as the source of 5α-reductase.

(2) Assay

5α-reductase activity was determined by following the conversion oftestosterone to 5α-dihydrotestosterone (DHT). In brief, buffer (100 mMTris-citrate, pH5.0), 1 mM NADPH and human prostatic 5α-reductase (0.4-1mg protein) were placed in test tubes. After addition of test compounds(dissolved in 5 μl in DMSO or EtOH) or solvents to the tubes, thesolutions were preincubated at room temperature for 10 min. Thereactions were initiated by addition of 1 μM ¹⁴ C-testosterone to afinal volume of 0.5 ml. Following 30 min incubation at 37° C., thereactions were stopped by addition of 5 ml dichloromethane. Aftercentrifugation at 1000 rpm for 5 min, the organic phase (bottom) wascollected and the volume reduced to ˜100 μl in a 42° C. water bath. Thesolutions were applied to silica plates and the plates were developed inchloroform/ethyl acetate (3:1) at room temperature. The radioactivityprofiles were determined by a BIOSCAN imaging scanner. The silica insections identified by BIOSCAN and counted in a scintillation counter.Enzyme activity was calculated from the percent of recovered radio labelconverted to the product DHT.

The results are shown in the table 1 and 2.

    ______________________________________           Ex.No.                 IC.sub.50 (μM)    ______________________________________           2     0.024            3(1) 0.020            3(2) 0.019            3(5) 0.21            3(8) 0.024           3(16) 0.17           3(18) 0.45           3(20) 0.13           3(22) 0.84           3(41) 0.098           3(47) 0.056           3(50) 0.16           3(54) 0.023           3(55) 0.024           3(62) 0.041           3(70) 0.17           3(77) 0.25           3(82) 0.63           3(83) 0.092    ______________________________________

                  TABLE 2    ______________________________________     ##STR57##           R      IC.sub.50 (μM)    ______________________________________           methyl 8.0           t-butyl                  0.4           iodo   0.44           hexyloxy                  0.17           isobutyl                  0.074    ______________________________________

Toxicity

The toxicity of a compound of the present invention of the formula (Ia)are very low and therefore, it may be estimated to be safe forpharmaceutical use.

Application for Pharmaceuticals

A compound of the present invention of the formula (Ia) and non-toxicsalts thereof are useful for 5α-reductase inhibitors.

5α-Reductase inhibitors are useful for prevention and/or treatment ofdiseases induced by the excess generation of dihydrotestosterone inmammals, especially human. The diseases such as above, for example, arealopecia (e.g. androgenic alopecia), acnes, hypertrophy of prostate andprostatic cancer.

For the purpose above described, the compounds of the formula (Ia) and(Ib), of the present invention and non-toxic salts thereof may benormally by administered systemically or locally usually by oral orparenteral administration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person are generally between 1 mg and 1000 mg, byoral administration, up to several times per day, and between 100 μg and100 mg, by parenteral administration (preferable intravenousadministration), up to several times per day, or continuousadministration between 1 and 24 hrs. per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

When administration of the compounds of the present invention, it isused as solid compositions, liquid compositions or other compositionsfor oral administration, as injections, liniments or suppositories etc.for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders, and granules.

Capsules include hard capsules and soft capsules.

In such compositions, one or more of the active compound(s) is or areadmixed with at least one inert diluent (such as lactose, mannitol,mannit, glucose, hydroxypropyl cellulose, microcrystalline cellulose,starch, polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.).The compositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g. lubricating agents (such asmagnesium stearate etc.), disintegrating agents (such as cellulosecalcium glycolate, etc.), stabilizing agents, and assisting agents fordissolving such as glutamic acid, aspartic acid etc.).

The tablets or pills may, if desired, be coated with a film of gastricor enteric material (such as sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate, etc.), or be coated with morethan two films. And further, coating may include containment withincapsules of absorbable materials such as gelatin.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, syrups and elixirs. Insuch compositions, one or more of the active compound(s) is or arecontained in inert diluent(s) commonly used in the art (purified water,ethanol etc.). Besides inert diluents, such compositions may alsocomprise adjuvants (such as wetting agents, suspending agents, etc.),sweetening agents, flavouring agents, perfuming agents, and preservingagents.

Other compositions for oral administration included spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s). Spray compositions may comprise additionalsubstances other than inert diluents: e.g. stabilizing agents (sodiumsulfate etc.), isotonic buffer (sodium chloride, sodium citrate, citricacid, etc.). For preparation of such spray compositions, for example,the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 may beused.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. Aqueous solutions,suspensions include distilled water for injection and physiological saltsolution. Non-aqueous solutions, suspensions include propylene glycol,polyethylene glycol, vegetable oil such as olive oil, alcohol such asethanol, POLYSORBATE80 (registered trade mark), etc.

Injections may comprise additional other than inert diluents: e.g.preserving agents, wetting agents, emulsifying agents, dispersingagents, stabilizing agent, assisting agents such as assisting agents fordissolving (glutamic acid, aspartic acid, etc.).

They may be sterilized for example, by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions or by irradiation. They may also be manufactured in theform of sterile solid compositions and which may be dissolved in sterilewater or some other sterile diluent(s) for injection immediately beforeused.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments, ointment, suppositories for rectaladministration and pessaries for vaginal administration which compriseone or more of the active compound(s) and may be prepared by per seknown methods.

Compositions for dermal administration; especially for the treatment andprevention of alopecia and acne, include liquids for external use suchas lotions, tonics, sprays, solutions, suspensions, emulsions andliniments such as ointments, gels and creams.

Such compositions may comprise one or more active ingredient(s) and atleast one inert diluent(s), for example, distilled water, a loweralcohol such as ethanol, a higher alcohol such as cetanol, a polyalcohol such as polyethylene glycol, propylene glycol, a cellulosederivative such as hydroxypropyl cellulose, animal or plant fats,petroleum jelly (e.g. as sold under the Trademark "VASELINE"), wax,silicone, a vegetable oil, such as olive oil, a surfactant, or zincoxide.

Besides inert diluents, such compositions may also comprise adjuvants(e.g. wetting agents, suspending agents, perfuming agents, preservingagents).

REFERENCE EXAMPLE AND EXAMPLE

The following examples illustrate the present invention, but not limitthe present invention.

The solvents in the parentheses show the developing or eluting solventsand the rations of the solvents used are by volume in chromatographicseparations.

Unless otherwise specified, "NMR" was measured in a d-chloroform (CDCl₃)solution and "IR" was measured by the KBr disk method respectively.

Reference example 1 ##STR58##

To a mixture of 15.0 g of aluminum chloride in 100 ml of chloroform wasadded 10.9 g of 4-biphenyl carbonyl chloride. Slowly, 5.3 ml of2-thiophenylacetonitrile was added to the mixture. The precipitate whichformed was broken up, and the mixture was heated to reflux. Afterapproximately four hours, heating was stopped. The mixture was thenpoured onto ice, and 300 ml of chloroform followed by 50 ml of conc.hydrochloric acid was added. The mixture was stirred to break up as muchresidue as possible. The organic layer separated was washed with dilutehydrochloric acid, followed by dilute sodium bicarbonate solution, driedover anhydrous potassium carbonate, and filtered. The filtrate wasconcentrated and purified on silica gel chromatography to obtain aftertrituration with ether 3.7 g of the desired product.

mp=181°-183° C.

NMR: δ3.99 (s, 2H), 7.17 (d, 1H), 7.36-7.77 (m, 8H), 7.87-7.98 (m, 2H).

Example 1 ##STR59##

To a solution of 2.26 g of 4'-ethyl-4-biphenyl carboxylic acid in 50.0ml of chloroform was added 1.0 ml of oxalyl chloride, followed by twodrops of dimethylformamide. The mixture was heated to reflux with theexclusion of moisture. After a period of one hour, the mixture wasconcentrated. To the concentrate was added 1.53 g of methyl1-methyl-2-pyrroleacetate and 20.0 ml of anhydrous m-xylene. The mixturewas again heated to reflux with the exclusion of moisture. After aperiod of 24 hours, heating was stopped. The mixture was thenconcentrated, taken up in chloroform, washed with dilute sodiumhydroxide solution, dried over potassium carbonate, and concentrated.This concentrate was purified on silica gel eluted with chloroform toyield 1.47 g of the desired product.

mp=124°-126° C.

NMR: δ1.28 (t, 3H), 2.71 (q, 2H), 3.73 (s, 2H), 3.75 (s, 3H), 3.97 (s,3H), 6.13 (d, 1H), 6.74 (d, 1H), 7.30 (d, 2H), 7.51-7.70 (m, 4H), 7.87(d, 2H).

Example 2 ##STR60##

To a solution of 1.25 g of the compound obtained in example 1 in 90.0 mlof methanol was added 7.0 ml of 1.0N sodium hydroxide solution, and themixture was stirred overnight. The mixture was then concentrated. Theconcentrate was taken up in warm water, treated with 10.0 ml of 1.0Nhydrochloric acid, and extracted with chloroform. The organic extractwas dried over anhydrous magnesium sulfate, and filtered. The filtratewas concentrated, and triturated in ether-hexane to yield 1.0 g of thedesired product.

mp=194°-196° C.

NMR: δ1.29 (t, 3H), 2.72 (q, 2H), 3.80 (s, 2H), 3.99 (s, 3H), 6.18 (d,1H), 6.77 (d, 1H), 7.31 (d, 2H), 7.51-7.72 (m, 4H), 7.88 (d, 2H).

IR: ν3020, 1694, 1628, 1600, 1481, 1458, 1380, 1267, 1239, 1194 cm⁻¹.

Example 3(1)-3(93)

The following compounds were obtained by the same procedure as a seriesof reaction of example 1→example 2, using a corresponding carboxylicacid or the compound of reference example 1 or a corresponding nitrilecompound instead of 4'-ethyl-4-biphenyl carboxylic acid and acorresponding compound instead of methyl 1-methyl-2-pyrroleacetate inexample 1.

Example 3(1) ##STR61##

NMR: δ1.43 (m, 5H), 1.87 (m, 5H), 2.58 (m, 1H), 3.77 (s, 2H), 3.95 (s,3H), 6.15 (d, 1H), 6.70 (d, 1H), 7.26 (d, 2H), 7.72 (d, 2H).

IR: ν2925, 1696, 1609, 1481, 1453, 1375, 1262, 886, 756 cm⁻¹.

Example 3(2) ##STR62##

NMR: δ3.79 (s, 2H), 3.99 (s, 3H), 6.17 (d, 1H), 6.76 (d, 1H), 7.34-7.53(m, 3H), 7.60-7.72 (m, 4H), 7.85-7.93 (m, 2H).

IR: ν3030, 1715, 1624, 1603, 1488, 1456, 1378, 1266 cm⁻¹.

Example 3(3) ##STR63##

NMR: δ3.77 (s, 2H), 3.96 (s, 3H), 4.06 (s, 2H), 6.14 (d, 1H), 6.69 (d,1H), 7.14-7.40 (m, 7H), 7.67-7.80 (m, 2H).

IR: ν3030, 1711, 1628, 1481, 1455, 1371, 1265, 1231 cm⁻¹.

Example 3(4) ##STR64##

NMR: δ3.78 (s, 2H), 3.98 (s, 3H), 6.15 (d, 1H), 6.70 (d, 1H), 7.42-7.63(m, 4H), 7.79 (d, 2H), 7.96 (m, 2H), 8.16 (s, 1H).

IR: ν3060, 1705, 1654, 1629, 1487, 1453, 1377, 1252 cm⁻¹

Example 3(5) ##STR65##

NMR: δ3.79 (s, 2H), 4.00 (s, 3H), 6.18 (d, 1H), 6.71 (d, 1H), 7.42-7.90(m, 9H).

IR: ν3060, 1694, 1651, 1628, 1492, 1456, 1398, 1278 cm⁻¹.

Example 3(6) ##STR66##

NMR: δ3.75 (s, 2H), 3.94 (s, 3H), 6.12 (d, 1H), 6.69 (d, 1H), 7.00-7.55(m, 9H).

IR: ν3200, 1730, 1697, 1609, 1575, 1487, 1453, 1375, 1269, 1240, 1197,1140 cm⁻¹

Example 3(7) ##STR67##

NMR: δ3.77 (s, 2H), 3.94 (s, 3H), 6.14 (d, 1H), 6.69 (d, 1H), 6.95-7.46(m, 7H), 7.81 (m, 2H).

IR: ν2950, 1720, 1593, 1561, 1485, 1448, 1376, 1238, 1179 cm⁻¹.

Example 3(8) ##STR68##

NMR: δ3.77 (s, 2H), 3.94 (s, 3H), 5.14 (s, 2H), 6.13 (d, 1H), 6.68 (d,1H), 7.04 (d, 2H), 7.43 (m, 5H), 7.83 (d, 2H).

IR: ν3065-2915, 1697, 1656, 1622, 1262, 888, 760 cm ⁻¹.

Example 3(9) ##STR69##

NMR (DMSO-d₆): δ7.72 (2H, d), 7.38 (2H, d), 7.24 (2H, d), 7.11 (2H, d),6.56 (1H, d), 6.09 (1H, d), 5.15 (2H, s), 3.80 (3H, s), 3.76 (2H, s),2.61 (2H, q), 1.18 (3H, t).

IR: ν3015, 2870, 1695, 1622, 1601, 1482, 1458, 1380, 1271, 1241 cm⁻¹.

Example 3(10) ##STR70##

NMR: δ7.82 (2H, d), 7.37 (2H, d), 7.27 (2H, d), 7.02 (2H, d), 6.67 (1H,d), 6.13 (1H, d), 5.09 (2H, s), 3.93 (3H, s), 3.79 (2H, s), 2.93 (1H,m), 1.26 (6H, d).

IR: ν3425, 2960, 1697, 1622, 1601, 1481, 1456, 1379, 1270, 1243, 880,759 cm⁻¹.

Example 3(11) ##STR71##

NMR (DMSO-d₆): δ7.73 (2H, d), 7.37 (2H, d), 7.23 (2H, d), 7.12 (2H, d),6.57 (1H, d), 6.11 (1H, d), 5.15 (2H, s), 3.80 (3H, s), 3.78 (3H, s),2.59 (2H, t), 1.56 (2H, m), 1.32 (2H, m), 0.90 (3H, t).

IR: ν3015, 2855, 1695, 1622, 1601, 1482, 1458, 1396, 1272, 1241 cm⁻¹.

Example 3(12) ##STR72##

NMR: δ7.83 (2H, d), 7.41 (4H, m), 7.01 (2H, d), 6.68 (1H, d), 6.15 (1H,d), 5.10 (2H, s), 3.94 (3H, s), 3.77 (2H, s), 1.38 (9H, s).

IR: ν2965, 1710, 1617, 1478, 1454, 1376, 1302, 1267, 1243, 1152, 1015,886, 818, 756 cm⁻¹.

Example 3(13) ##STR73##

NMR: δ3.71 (s, 2H), 3.87 (s, 3H), 4.10 (s, 2H), 6.15 (d, 1H,), 7.11 (d,1H), 7.27-7.63 (m, 9H).

IR: ν3030, 1734, 1559, 1487, 1450, 1375, 1186, 1154 cm⁻¹.

Example 3(14) ##STR74##

NMR: δ3.81 (s, 2H), 4.01 (s, 3H), 6.18 (d, 1H), 6.76 (d, 1H), 7.56 (m,2H), 7.91 (m, 4H), 8.32 (s, 1H).

IR: ν3050, 2950, 1696, 1619, 1484, 1457, 1378, 1279, 1238, 770, 738cm⁻¹.

Example 3(15) ##STR75##

NMR: δ3.75 (s, 2H), 3.91 (s, 3H), 3.95 (s, 3H), 5.19 (s, 2H), 6.08 (d,1H), 6.50 (d, 1H), 6.92 (m, 1H), 7.26-7.52 (m, 7H).

Example 3(16) ##STR76##

NMR: δ7.55-7.20 (6H, m),6.87-6.74 (2H, m), 6.47 (1H, d,), 6.09 (1H, d),5.10 (2H, s), 3.99 (3H, s), 3.76 (3H, s), 2.38 (3H, s).

IR: ν3035, 2920, 1711, 1616, 1570, 1497, 1452, 1421, 1397, 1377, 1311,1263, 1235, 1192, 1102, 993, 870, 847, 752 cm⁻¹.

Example 3(17) ##STR77##

NMR: δ7.50-7.30 (5H, m),7.20 (2H, d), 6.75 (2H, d), 6.46 (1H, d), 6.07(1H, d), 5.11 (2H, s), 4.01 (3H, s), 3.75 (3H, s), 2.27 (3H, s), 2.25(3H, s).

IR: ν3030, 1721, 1630, 1592, 1480, 1455, 1370, 1261, 1238, 1217, 1187,1067, 795, 761, 736 cm⁻¹.

Example 3(18) ##STR78##

NMR: δ3.97 (s, 2H), 7.07 (d, 1H), 7.38-7.56 (m, 3H), 7.57-7.79 (m, 5H),7.90-8.02 (m, 2H).

IR: ν3060, 2920, 1696, 1619, 1450, 1405, 1315, 1222 cm⁻¹.

Example 3(19) ##STR79##

NMR (CDCl₃ /DMSO-d₆ (2 drops)): δ3.83 (s, 2H), 6.65 (d, 1H), 7.23 (d,1H), 7.30-8.09 (m, 9H).

Example 3(20) ##STR80##

NMR: δ3.78 (s, 2H), 3.98 (s, 3H), 6.17(d, 1H), 6.71 (d, 1H), 7.35-7.41(m, 1H), 7.52-7.76 (m, 4H), 7.93-8.07 (m, 2H).

IR: ν1716, 1640, 1490, 1456, 1379, 1199, 1100, 746 cm⁻¹.

Example 3(21) ##STR81##

NMR: δ1.95-2.13 (m, 2H), 2.64-2.81 (m, 4H), 3.70 (s, 2H), 3.88 (s, 3H),6.09 (d, 1H), 6.86 (d, 1H), 7.19-7.28 (m, 5H).

IR: ν2945, 1704, 1640, 1485, 1456, 1421, 1380, 1256, 990, 917, 701 cm⁻¹.

Example 3(22) ##STR82##

NMR: δ1.70 (m, 4H), 2.64 (t, 2H), 2.77 (t, 2H), 3.70 (s, 2H), 3.87 (s,3H), 6.10 (d, 1H), 6.92 (d, 1H), 7.10-7.33 (m, 5H).

IR: ν2600-4000, 1693, 1646, 1458, 1258, 1259, 752, 696 cm⁻¹.

Example 3(23) ##STR83##

NMR: δ0.89 (t, 3H), 1.32 (m, 8H), 1.68 (m, 2H), 2.65 (t, 2H), 3.79 (s,2H), 3.98 (s, 3H), 6.17 (d, 1H), 6.75 (d, 1H), 7.26 (d, 2H), 7.57 (d,2H), 7.65 (d, 2H), 7.85 (d, 2H),

IR: ν3000-3900, 2925, 1695, 1627, 1482, 1458, 1269, 1241 cm⁻¹.

Example 3(24) ##STR84##

NMR: δ3.95 (s, 2H), 7.00-7.50 (m, 8H), 7.52 (d, 1H,), 7.87 (d, 2H).

IR: ν3030, 1692, 1619, 1591, 1490, 1456, 1311, 1264, 1166 cm⁻¹

Example 3(25) ##STR85##

NMR (CDCl₃ /DMSO-d₆): δ3.63 (s, 2H), 3.66 (s, 3H), 6.62 (d, 1H), 7.22(d, 1H), 7.30-7.54 (m, 3H), 7.60-7.76 (m, 4H), 7.85-7.96 (m, 2H).

IR: ν3055, 1717, 1610, 1590, 1518, 1430, 1353, 1251, 1199 cm⁻¹.

Example 3(26) ##STR86##

NMR (DMSO-d₆): δ7.90-7.70 (6H, m), 7.64 (1H, d), 7.56-7.40 (3H, m), 6.89(1H, d), 6.74 (1H, d), 6.51 (1H, d), 4.03 (3H, s).

IR: ν3030, 1680, 1615, 1516, 1469, 1446, 1376, 1312, 1255, 1211, 960,888, 745 cm⁻¹.

Example 3(27) ##STR87##

NMR: δ7.86 (2H, d), 7.70-7.30 (7H, m), 6.72 (1H, d), 6.01 (1H, d), 3.98(3H, s), 3.00 (2H, m), 2.79 (2H, m).

IR: ν3425, 3030, 1697, 1615, 1481, 1451, 1406, 1374, 1263, 1224, 1152,887, 746, 695 cm⁻¹.

Example 3(28) ##STR88##

NMR: δ7.85 (2H, d), 7.65 (4H, m), 7.50-7.40 (3H, m), 6.73 (1H), 6.01(1H, d), 3.96 (3H, s), 2.73 (2H, t), 2.50 (2H, t), 2.04 (2H, m).

IR: ν3030, 1708, 1620, 1478, 1437, 1426, 1399, 1372, 1291, 1258, 1157,1047, 891, 760 cm⁻¹.

Example 3(29) ##STR89##

NMR: δ7.88 (2H, d), 7.65 (4H, m), 7.55-7.40 (3H, m), 7.40-7.15 (3H, m),7.02 (2H, d), 6.85 (1H, d), 6.27 (1H, d), 5.80 (2H, s), 3.65 (2H, s).

IR: ν3060, 1717, 1618, 1537, 1478, 1452, 1424, 1390, 1269, 1204, 1152,1053, 882, 848, 746 cm⁻¹.

Example 3(30) ##STR90##

NMR: δ7.87 (2H, d), 7.65 (4H, m), 7.50-7.35 (3H, m), 6.73 (1H, d), 6.01(1H, d), 3.96 (3H, s), 2.68 (2H, t), 2.45 (2H, t,), 1.78 (4H, m).

IR: ν3025, 2875, 1699, 1610, 1479, 1456, 1432, 1406, 1374, 1314, 1257,1207, 1174, 1035, 1005, 961, 938, 881, 852, 786, 751, 728, 700 cm⁻¹.

Example 3(31) ##STR91##

NMR: δ7.80 (2H, d), 7.37 (2H, d), 7.26 (2H, d), 7.01 (2H, d), 6.66 (1H,d), 5.98 (1H, d), 5.09 (2H, s), 3.92 (3H, s), 2.93 (1H, m), 2.72 (2H,t), 2.50 (2H, t), 2.03 (2H, m), 1.26 (6H, d).

IR: ν3035, 2890, 1707, 1619, 1480, 1458, 1422, 1375, 1308, 1260, 1172,1046, 891, 751 cm⁻¹.

Example 3(32) ##STR92##

NMR: δ7.80 (2H, d), 7.37 (2H, d), 7.26 (2H, d), 7.01 (2H, d), 6.66 (1H,d), 5.97 (1H, d), 5.09 (2H, s), 3.91 (3H, s), 2.93 (1H, m), 2.66 (2H,t), 2.44 (2H, t), 1.76 (4H, m), 1.26 (6H,d).

IR: ν2966, 1697, 1607, 1479, 1449, 1373, 1314, 1251, 889 cm⁻¹.

Example 3(33) ##STR93##

NMR: δ3.71 (s, 2H), 3.85 (s, 3H), 6.09 (d, 1H), 6.61 (d, 2H), 6.88-7.50(m, 9H).

IR: ν2900-3100, 1708, 1622, 1487, 1454, 1378, 1232, 747 cm⁻¹.

Example 3(34) ##STR94##

NMR: δ1.20-2.10 (m, 10H), 3.76 (s, 2H), 3.93 (s, 3H), 4.36 (m, 1H), 6.13(d, 1H), 6.68 (d, 1H), 6.91 (d, 2H), 7.80 (d, 2H).

Example 3(35) ##STR95##

NMR (DMSO-d₆): δ3.64 (s, 2H), 3.86 (s, 3H), 6.10 (d, 1H), 6.63 (d, 1H),7.27 (d, 4H), 7.83 (d, 2H), 8.32 (d, 2H).

IR: ν3080, 2930, 1707, 1619, 1635, 1515, 1486, 1341, 1251, 1165, 887,751 cm⁻¹.

Example 3(36) ##STR96##

NMR: δ3.74 (s, 2H), 3.92 (s, 3H), 5.55 (s, 1H), 6.03 (d, 1H), 6.45 (d,1H), 6.70 (m, 1H), 6.97 (s, 1H), 7.08-7.40 (m, 13H).

IR: ν3400-3060, 1729, 1590, 1531, 1487, 1451, 1375, 747, 700 cm⁻¹.

Example 3(37) ##STR97##

NMR: δ3.70 (s, 2H), 3.89 (s, 3H), 4.68 (s, 4H), 5.98 (d, 1H), 6.46 (d,1H), 6.89 (bd, 1H), 7.08-7.36 (m, 13H).

IR: ν3200-2900, 1745, 1717, 1595, 1569, 1492, 1451, 1364, 1261, 749,739, 697 cm⁻¹.

Example 3(38) ##STR98##

NMR: δ3.59 (s, 4H), 3.62 (s, 2H), 3.74 (s, 2H), 3.94 (s, 3H), 6.11 (d,1H), 6.66 (d, 1H), 7.20-7.55 (m, 12H), 7.74 (d, 2H).

IR: ν3060, 1730, 1619, 1558, 1403, 1452, 1374 cm⁻¹.

Example 3(39) ##STR99##

NMR (DMSO-d₆): δ3.80 (s, 2H), 3.85 (s, 3H), 6.14 (d, 1H), 6.68 (s, 1H),7.42-7.66 (m, 5H), 7.99 (m, 3H), 8.20 (s, 1H), 10.43 (s, 1H).

IR: ν3200-2955, 1733, 1675, 1578, 1549, 1473, 1376, 1262, 1201, 748cm⁻¹.

Example 3(40) ##STR100##

NMR (DMSO-d₆): δ3.80 (s, 2H), 3.83 (s, 3H), 6.14 (d, 1H), 6.62 (d, 1H),7.58 (m, 3H), 7.77 (m, 2H), 8.00 (m, 4H), 10.53 (s, 1H).

IR: ν3500-2800, 1731, 1653, 1596, 1518, 1488, 1263, 758, 708 cm⁻¹.

Example 3(41) ##STR101##

NMR: δ3.76 (s, 2H), 3.95 (s, 3H), 4.14 (s, 2H), 6.13 (d, 1H), 6.65 (d,1H), 7.17-7.42 (m, 7H), 7.70 (d, 2H).

IR: ν3060, 1701, 1624, 1482, 1377, 1264, 1232 cm⁻¹.

Example 3(42) ##STR102##

NMR: δ3.78 (s, 2H), 3.96 (s, 3H), 4.14 (s, 2H), 6.13 (d, 1H), 6.51 (d,1H), 7.19-7.68 (m, 9H).

Example 3(43) ##STR103##

NMR: δ3.70 (s, 2H), 3.98 (s, 3H), 4.11 (s, 2H), 6.14 (d, 1H), 6.62 (d,1H), 7.04 (d, 2H), 7.42-7.49 (m, 5H), 7.66 (d, 2H).

IR: ν1719, 1626, 1480, 1375, 1261, 1209, 1045, 885, 750 cm⁻¹.

Example 3(44) ##STR104##

NMR: δ3.77 (s, 2H), 3.94 (s, 3H), 4.10 (s, 2H), 6.12 (d, 1H), 6.53 (d,1H), 7.13-7.75 (m, 9H).

IR: ν1724, 1618, 1616, 1591, 1489, 1451, 1379, 1273, 1179, 753 cm⁻¹.

Example 3(45) ##STR105##

NMR: δ7.72 (2H, d), 7.32-7.15 (7H, m), 6.68 (1H, d), 6.14 (1H, d), 3.97(3H, s), 3.77 (2H, s), 2.97 (4H, m).

IR: ν3065, 2965, 1716, 1622, 1559, 1487, 1457, 1421, 1376, 1267, 1232,886 cm⁻¹.

Example 3(46) ##STR106##

NMR: δ3.70 (2, 2H), 3.87 (s, 3H), 6.15 (d, 1H), 6.68 (d, 1H), 7.37 (m,3H), 7.54 (m, 2H), 7.57 (d, 2H), 7.78 (d, 2H).

IR: ν3015, 1698, 1620, 1592, 1486, 1456, 1378, 1264 cm⁻¹.

Example 3(47) ##STR107##

NMR: δ7.75-7.65 (6H, m), 7.46-7.32 (5H, m), 6.64 (1H, d), 6.15 (1H, d),3.86 (3H, s), 3.82 (2H, s).

IR: ν3030, 1732, 1700, 1570, 1541, 1489, 1457, 1420, 1398, 1268, 1242,960, 887, 762, 685 cm⁻¹.

Example 3(48) ##STR108##

NMR: δ1.35-1.48 (m, 2H), 1.60-1.80 (m, 4H), 2.61 (t, 2H), 2.75 (t, 2H),3.71 (s, 2H), 3.88 (s, 3H), 6.10 (d, 1H), 6.92 (d, 1H), 7.15-7.30 (m,5H).

IR: ν2930, 1698, 1635, 1490, 1462, 1420, 1238, 917, 774, 746, 694 cm⁻¹.

Example 3(49) ##STR109##

NMR: δ3.79 (s, 2H), 3.99 (s, 3H), 6.16 (d, 1H), 6.36 (t, 2H), 6.72 (d,1H), 7.13 (t, 2H), 7.43-7.68 (m, 3H), 7.81 (s, 1H).

IR: ν2955, 1743, 1572, 1490, 1380, 1242, 1168, 746 cm⁻¹

Example 3(50) ##STR110##

NMR: δ3.78 (s, 2H), 3.98 (s, 3H), 6.19 (d, 1H), 6.40 (m, 2H), 6.73 (d,1H), 7.17 (m, 2H), 7.48 (d, 2H), 7.92 (d, 2H).

IR: ν3100-2955, 1698, 1646, 1621, 1331, 1267, 884, 758, 717 cm⁻¹.

Example 3(51) ##STR111##

NMR (DMSO-d₆): δ3.24 (s, 2H), 3.81 (s, 3H), 4.71 (s, 4H), 5.87 (d, 1H),6.49 (d, 1H), 6.73 (d, 2H), 7.29-7.43 (m, 4H), 7.73 (d, 2H).

IR: ν3500-2800, 1606, 1471, 1367, 1274, 1181, 1148, 883, 758 cm⁻¹.

Example 3(52) ##STR112##

NMR: δ2.07 (s, 6H), 3.80 (s, 2H), 3.99 (s, 3H), 5.93 (s, 2H), 6.18 (d,1H), 6.76 (d, 1H), 7.28 (d, 2H), 7.90 (d, 2H).

IR: ν3200, 2800, 1718, 1616, 1406, 1263, 1226, 884 cm⁻¹

Example 3(53) ##STR113##

NMR: δ3.78 (s, 2H), 3.99 (s, 3H), 6.15 (d, 1H), 6.73 (d, 1H), 7.07 (m,1H), 7.25-7.52 (m, 3H), 7.62-7.82 (m, 2H), 8.01 (s, 1H).

IR: ν3105, 1734, 1699, 1623, 1595, 1489, 1454, 1375 cm⁻¹.

Example 3(54) ##STR114##

NMR (CDCl₃ /DMSO-d₆): δ3.70 (s, 2H), 3.87 (s, 3H), 6.14 (d, 1H), 6.72(d, 1H), 7.14 (M, 1H), 7.32-7.48 (m, 2H), 7.68 (m, 2H), 7.83 (m, 2H).

IR: ν2950, 1735, 1699, 1626, 1600, 1483, 1456, 1379, 1259 cm⁻¹.

Example 3(55) ##STR115##

NMR: δ3.70 (s, 2H), 3.97 (s, 3H), 6.15 (d, 1H), 6.70 (d, 1H), 7.06 (d,1H), 7.15 (d, 1H), 7.57 (d, 2H), 7.81 (d, 2H).

IR: ν1695, 1622, 1484, 1458 1429, 1379, 1268, 979, 758 cm⁻¹.

Example 3(56) ##STR116##

NMR: δ0.82-0.93 (m, 2H), 1.22-1.39 (m, 8H), 1.59-1.75 (m, 2H), 2.66 (t,3H), 3.77 (s, 2H), 3.96 (s, 3H), 6.14 (d, 1H), 6.69 (d, 1H), 7.24 (d,2H), 7.72 (d, 2H).

IR: ν1735, 1697, 1622, 1487, 1457, 1378, 1269, 1238, 887 cm⁻¹.

Example 3(57) ##STR117##

NMR: δ0.91 (t, 3H), 1.00-1.58 (m, 9H), 1.90 (m, 4H), 2.52 (m, 1H), 3.77(s, 2H), 3.96 (s, 3H), 6.14 (d, 1H), 6.70 (d, 1H), 7.28 (d, 2H), 7.75(d, 2H).

Example 3(58) ##STR118##

NMR: δ2.41 (s, 3H), 3.79 (s, 2H), 3.98 (s, 3H), 6.16 (d, 1H), 6.75 (d,1H), 7.27 (d, 2H), 7.54 (d, 2H), 7.65 (d, 2H), 7.86 (d, 2H).

IR: ν1730, 1617, 1588, 1486, 1451, 1400, 1379, 1264, 1199, 877, 814, 761cm⁻¹.

Example 3(59) ##STR119##

NMR: δ2.29 (s, 3H), 3.79 (s, 2H), 3.99 (s, 3H), 6.17 (d, 1H), 6.78 (d,1H), 7.28 (m, 4H), 7.40 (d, 2H), 7.85 (d, 2H).

IR: ν3020, 1731, 1700, 1618, 1481, 1453, 1406, 1376, 1262 cm⁻¹.

Example 3(60) ##STR120##

NMR: δ0.98 (t, 3H), 1.67 (q, 2H), 2.64 (t, 2H), 3.79 (s, 2H), 3.99 (s,3H), 6.19 (d, 1H), 6.75 (d, 1H), 7.28 (d, 2H), 7.54-7.68 (m, 4H), 7.87(d, 2H).

IR: ν2955, 1698, 1672, 1601, 1401, 1457, 1398, 1267, 761 cm⁻¹.

Example 3(61) ##STR121##

NMR (DMSO-d₆): δ3.83 (s, 5H), 3.86 (s, 3H), 6.16 (d, 1H), 6.66 (d, 1H),7.08 (d, 2H), 7.72 (d, 2H), 7.78 (m, 4H).

IR: ν3035, 2910, 1733, 1695, 1627, 1600, 1525, 1483, 1458, 1378, 1295,1268 cm⁻¹.

Example 3(62) ##STR122##

NMR: δ3.79 (s, 2H), 3.98 (s, 3H), 6.17 (d, 1H), 6.74 (d, 1H), 7.15 (m,2H), 7.63 (m, 4H), 7.89 (m, 2H).

IR: ν3020, 1732, 1698, 1624, 1484, 1456, 1378, 1266 cm⁻¹.

Example 3(63) ##STR123##

NMR (DMSO-d₆): δ3.75 (s, 2H), 3.86 (s, 3H), 6.12 (d, 1H), 6.63 (d, 1H),7.56 (d, 4H), 7.77 (d, 4H).

IR: ν3035, 1713, 1621, 1633, 1480, 1453, 1376, 1265, 885, 822, 760 cm⁻¹.

Example 3(64) ##STR124##

NMR: δ3.79 (s, 2H), 3.99 (s, 3H), 6.17 (d, 1H), 6.73 (d, 1H), 7.23 (m,1H), 7.47 (m, 1H), 7.60 (d, 2H), 7.65 (m, 1H), 7.87 (d, 2H).

IR: ν3020, 1732, 1701, 1621, 1484, 1455, 1379, 1266 cm⁻¹.

Example 3(65) ##STR125##

NMR: δ3.80 (s, 2H), 4.00 (s, 3H), 6.18 (d, 1H), 6.74 (d, 1H), 7.53-7.96(m, 8H).

IR: ν3030, 1731, 1690, 1625, 1483, 1455, 1378, 1333, 1259, 1179, 1123cm⁻¹.

Example 3(66) ##STR126##

NMR (DMSO-d₆): δ3.82 (s, 2H), 3.87 (s, 3H), 6.14-6.16 (d, 1H), 6.65-6.67(d, 1H), 7.86-8.01 (m, 8H).

IR: ν3050, 1713, 1620, 1486, 1454, 1397, 1376, 1325, 1265, 1168, 1124,1072, 885, 832, 764, 737 cm⁻¹.

Example 3(67) ##STR127##

NMR (DMSO-d₆): δ8.53 (1H, d), 8.26 (2H, m), 7.96-7.80 (5H, m), 6.66 (1H,d), 6.15 (1H, d), 3.87 (3H, s), 3.82 (2H, s).

IR: ν3100, 2995, 1732, 1619, 1530, 1455, 1377, 1348, 1264, 886, 771, 735cm⁻¹.

Example 3(68) ##STR128##

NMR (DMSO-d₆): δ2.63 (s, 3H), 3.79 (s, 2H), 3.86 (s, 3H), 6.14 (d, 1H),6.65 (d, 1H), 7.75-7.94 (m, 6H), 8.10 (d, 2H).

IR: ν3395, 2925, 1763, 1700, 1619, 1455, 1376, 1264, 885, 762 cm⁻¹.

Example 3(69) ##STR129##

NMR: δ7.85 (2H, d), 7.64 (4H, m), 7.51 (2H, d), 6.65 (1H, d), 6.09 (1H,d), 3.97 (3H, s), 3.73 (2H, s), 3.12 (3H, broad s), 3.05 (3H, broad s).

IR: ν3445, 3030, 1731, 1699, 1622, 1567, 1539, 1504, 1480, 1452, 1398,1377, 1264, 885, 837, 752 cm⁻¹.

Example 3(70) ##STR130##

NMR: δ7.94 (2H, d), 7.74-7.64 (4H, m), 7.53-7.43 (3H, m), 7.08 (1H, d),6.70 (1H, d), 4.30 (3H, s).

IR: ν3060, 1702, 1653, 1630, 1601, 1507, 1447, 1372, 1258, 887, 745cm⁻¹.

Example 3(71) ##STR131##

NMR (DMSO-d₆): δ7.90-7.73 (7H, m), 7.56-7.43 (3H, m), 7.21 (1H, d), 3.94(3H, s).

IR: ν3113, 2960, 1678, 1629, 1601, 1535, 1496, 1467, 1400, 1373, 1288,1249, 1206, 1134, 1104, 1077, 886, 749 cm⁻¹.

Example 3(72) ##STR132##

NMR (DMSO-d₆): δ7.96 (2H, d), 7.87 (2H, m), 7.79 (2H, d), 7.58-7.45 (3H,m), 6.86 (2H, m).

IR: ν3265, 1691, 1602, 1406, 1273, 1211, 887, 743 cm⁻¹.

Example 3(73) ##STR133##

NMR (DMSO-d₆): δ7.93-7.75 (6H, m), 7.57-7.40 (4H, m), 7.12 (1H, s).

IR: ν3330, 1697, 1673, 1620, 1447, 1387, 1280, 1235, 1194, 1123, 885,746 cm⁻¹.

Example 3(74) ##STR134##

NMR: δ9.95 (1H, br.), 8.18 (2H, d), 7.71-7.61 (4H, m), 7.50-7.37 (3H,m), 7.19 (1H, s), 3.87 (3H, s), 3.64 (2H, s).

IR: ν3030, 1730, 1703, 1648, 1600, 1472, 1432, 1375, 1267, 1226, 1195,1160, 905, 752 cm⁻¹.

Example 3(75) ##STR135##

NMR (CDCl₃ +2 drops of DMSO-d₆): δ8.28 (2H, d), 7.87 (1H, s), 7.72 (2H,d), 7.65 (2H, m), 7.52-7.40 (3H, m), 4.31 (3H, s).

IR: ν3135, 2965, 1707, 1652, 1600, 1518, 1407, 1259, 1195, 907, 752cm⁻¹.

Example 3(76) ##STR136##

NMR: δ0.87 (s, 9H), 0.95-2.00 (m, 9H), 2.85-3.05 (m, 1H), 3.71 (s, 2H),3.88 (s, 3H), 6.10-6.12 (d, 1H), 6.96-6.98 (d, 1H).

IR: ν2945, 1700, 1646, 1486, 1461, 1417, 1384, 1296, 1254, 989, 918,818, 765 cm⁻¹.

Example 3(77) ##STR137##

NMR: δ1.40-2.10 (m, 8H), 2.50-2.75 (m, 1H), 3.00-3.32 (m, 1H), 3.72 (twos, 2H), 3.87 (two s, 3H), 6.12 (two d, 1H), 7.00 (two d, 1H), 7.13-7.37(m, 5H).

IR: ν3060, 2930, 1733, 1638, 1489, 1453, 1305, 1248 cm⁻¹

Example 3(78) ##STR138##

NMR: δ1.72-2.08 (m,6H), 2.56-2.81 (m,9H), 3.70 (s,2H), 3.88 (s,3H), 6.09(d,1H), 6.88-7.00 (m,5H).

IR: ν2075, 1722, 1596, 1495, 1457, 1407, 1383, 1303, 1202, 1121, 1048,930, 771, 740, 669 cm⁻¹.

Example 3(79) ##STR139##

NMR (DMSO-d₆): δ3.80 (s, 2H), 3.86 (s, 3H), 6.13 (d, 1H), 6.64 (d, 1H),7.71 (s, 4H), 7.81 (s, 4H).

IR: ν3030, 1731, 1701, 1620, 1475, 1452, 1374, 1261, 882, 817, 757 cm⁻¹.

Example 3(80) ##STR140##

NMR (CDCl₃ +2 drops of DMSO-d₆): δ11.44 (1H, broad), 7.92 (2H, d), 7.66(4H, m), 7.52-7.38 (3H, m), 6.80 (1H, dd), 6.17 (1H, dd), 3.73 (2H, s).

IR: ν3275, 1713, 1593, 1494, 1425, 1275, 1238, 884, 777, 748 cm⁻¹.

Example 3(81) ##STR141##

NMR (DMSO-d₆): δ3.56 (s, 2H), 3.88 (s, 3H), 6.05 (d, 1H), 6.61 (d, 1H),7.50-7.63 (m, 4H), 7.73-7.85 (m, 3H)

IR: ν3505, 1713, 1619, 1589, 1483, 1453, 1371, 1261 cm⁻¹

Example 3(82) ##STR142##

NMR (DMSO-d₆): δ3.63 (s, 2H), 3.89 (s, 3H), 6.08 (d, 1H), 6.61 (d, 1H),7.65-7.95 (m, 7H).

IR: ν3445, 3065, 2950, 1714, 1618, 1585, 1481, 1451, 1371, 1260 cm⁻¹

Example 3(83) ##STR143##

NMR: δ2.32 (s, 3H), 3.79 (s, 2H), 3.98 (s, 3H), 6.17 (d, 1H), 6.77 (d,1H), 7.25-7.50 (m, 6H), 7.62-7.75 (m, 2H).

IR: ν2950, 1725, 1586, 1484, 1448, 1396, 1370, 1253, 1175 cm⁻¹

Example 3(84) ##STR144##

NMR: δ3.52 (s, 3H), 3.72 (s, 2H), 3.90 (s, 3H), 6.07 (d, 1H), 6.51 (d,1H), 7.05 (m, 2H), 7.18 (m, 3H), 7.34 (d, 2H), 7.55 (d, 2H).

IR: ν3055, 1730, 1618, 1587, 1489, 1372, 1295, 1275 cm⁻¹.

Example 3(85) ##STR145##

NMR (DMSO_(d6)): δ3.83 (s, 2H), 3.89 (s, 3H) 6.17 (d, 1H), 6.62 (d, 1H),7.13 (m, 1H), 7.38 (m, 2H), 7.82 (m, 4H), 8.07 (m, 2H), 10.41 (s, 1H).

IR: ν3340, 3055, 1714, 1664, 1598, 1534, 1486, 1440, 1373, 1322, 1258cm⁻¹.

Example 3(86) ##STR146##

NMR (DMSO_(d6)): δ3.89 (s, 5H), 6.01 (d, 1H), 6.45 (d, 1H), 6.54 (d,1H), 7.35 (m, 10H), 7.72-8.10 (m, 4H), 9.43 (d, 1H).

IR: ν3420, 1623, 1524, 1486, 1450, 1367, 1271, 1186 cm⁻¹.

Example 3(87) ##STR147##

NMR (DMSO_(d6)): δ2.87 and 2.92 (singles, total 3H), 3.82 (s, 2H), 3.86(s, 3H), 4.51 and 4.72 (singles, total, 2H), 6.14 (d, 1H), 6.63 (d, 1H),7.16-7.87 (m, 9H).

IR: ν3025, 1722, 1619, 1597, 1488, 1450, 1402, 1375, 1258, 1199 cm⁻¹.

Example 3(88) ##STR148##

NMR: δ3.76 (s, 2H), 3.98 (s, 3H), 4.67 (d, 2H), 6.14 (d, 1H), 6.52 (t,1H), 6.63 (d, 1H), 7.36 (m, 4H), 7.82 (m, 5H).

IR: ν3270, 3055, 1718, 1616, 1539, 1484, 1450, 1373, 1258, 1201 cm⁻¹.

Example 3(89) ##STR149##

NMR: δ3.06 (m, 4H), 3.71 (s, 2H), 3.89 (s, 3H), 6.10 (d, 1H), 6.93 (d,1H), 7.25 (m, 5H).

IR: ν3025, 2900, 1690, 1644, 1481, 1455, 1345, 1223, 969, 759 cm⁻¹.

Example 3(90) ##STR150##

mp 152°-155° C.

NMR: δ1.37 (d, 6H), 3.77 (s, 2H), 3.93 (s, 3H), 4.64 (m, 1H), 6.14 (d,1H), 6.68 (d, 1H), 6.90 (d, 2H), 7.80 (d, 2H).

IR: ν2960, 1725, 1602, 1557, 1487, 1455, 1380, 1297, 1196, 1150, 1047,888, 837, 756 cm⁻¹

Example 3(91) ##STR151##

mp 180°-185° C.

NMR: δ3.77 (s, 2H), 3.94 (s, 3H), 4.36-4.38 (m, 4H), 6.14 (d, 1H), 6.67(d, 1H), 6.94-7.01 (m, 5H), 7.26-7.37 (m, 2H), 7.83 (d, 2H).

IR: ν2955, 1695, 1624, 1599, 1496, 1455, 1328, 1299, 1272, 1240, 1174,945, 844, 784, 678 cm⁻¹.

Example 3(92) ##STR152##

mp 174°-178° C.

NMR: δ3.80 (s, 2H), 3.94 (s, 3H), 6.22 (d, 1H), 7.08 (d, 1H), 7.43 (m,2H), 7.87 (m, 2H), 7.96 (s, 1H).

IR: ν3039, 2955, 1697, 1609, 1511, 1451, 1374, 1262, 1180, 749 cm⁻¹

Example 3(93) ##STR153##

mp 182°-183° C.

NMR: δ3.80 (s, 2H), 3.97 (s, 3H), 6.24 (d, 1H), 7.26-7.73 (m, 6H).

IR: ν3065, 2960, 1692, 1600, 1542, 1451, 1373, 1224, 1194, 1136, 850,746 cm⁻¹.

Formulation example

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.

    ______________________________________    2- 5-(4-phenylbenzoyl)-1-methylpyrrol-2-yl! acetic acid                                5     g    Cellulose calcium gluconate (disintegrating agent)                                0.2   g    Magnesium stearate (lubricating agent)                                0.1   g    Microcrystalline cellulose  4.7   g    ______________________________________

What is claimed is:
 1. A pharmaceutical composition for the treatment ofdiseases induced by the excess generation of dihydrotestosterone inmammals, alopecia, acnes, hypertrophy of prostate and prostatic cancer,which comprises, as active ingredient, and effective amount of acompound of the formula (1a): ##STR154## wherein Z is pyrrole includednitrogen substituted by R⁴, thiophene, furan, imidazole includednitrogen substituted by R⁴, thiazole, oxazole, triazole includednitrogen substituted by R⁴, in whichR⁴ is hydrogen, C1-4 alkyl, phenylor phenyl(C1-4)alkyl; A is bond, C1-6 alkylene or C2-6 alkenylene; E isbond or C1-6 alkylene; D is benzene, C4-7 cycloalkane, naphthalene,benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane, ##STR155##in which m is 0 or 1, or benzene fused 4-7 membered heterocyclic ringconsisting of one nitrogen, one sulfur or one oxygen atom; R¹ ishydrogen or C1-4 alkyl; R² is hydrogen or C1-4 alkyl; n is 1-3; R³ each,independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro,methylthio, trifluoromethyl or cyano, (2)--Q--T--U--R⁵ in which Q isbond or C1-6 alkylene; T is bond, --O--, ##STR156## --S--, --SO₂ --,--NR⁷ -- or --NR⁷ CO--, in which R⁷ is hydrogen, C1-4 alkyl, phenyl orphenyl(C1-4)alkyl and nitrogen atom in --NR⁷ CO-- may be connected with--Q-- or --U--; U is bond, C1-6 alkylene, C2-6 alkyenylene, C2-6alkynylene or C1-6 alkylene --O--, in which oxygen atom can be connectedwith R⁵ only; R⁵ is (i) C4-7 cycloalkyl, (ii) phenyl, (iii)diphenylmethyl or (iv) 4-7 membered heterocyclic ring consisting of onenitrogen, one sulfur or one oxygen, or the benzene fused 4-7 memberedheterocyclic ring consisting of one nitrogen, one sulfur or one oxygen,or rings in (i), (ii), (iii), (iv) of R⁵ may be substituted by 1-3 ofC1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro orCOR⁶, in which R⁶ is C1-4 alkyl, NR⁸ R⁹, in which R⁸ and R⁹ each,independently, is hydrogen or C1-4 alkyl; or --Q--T--U--R⁵ is C7-10alkyl, C7-10 alkoxy; or non-toxic salts thereof, with the proviso that,the compounds wherein(i) T is --O--, or --NR⁷ --, and U is bond and R⁵is diphenylmethyl in --Q--T--U--R⁵ represented by R³, when Z isthiophene, E is bond and D is benzene or naphthalene, (ii) T is --O--,or --NR⁷ --, and U is C1-6 alkylene and R⁵ is phenyl or diphenylmethylin --Q--T--U--R⁵ represented by R³, when Z is thiophene, E is bond and Dis benzene or naphthalene, (iii) Z is pyrrole included nitrogensubstituted by R⁴, in which R⁴ is hydrogen, C1-3 alkyl or phenyl, A isbond or methylene, E is bond D is benzene, R² is hydrogen or methyl andR³ each, independently, is hydrogen or halogen, are excluded;with apharmaceutical carrier or coating.
 2. A method for the treatment ofdiseases induced by the excess generation of dihydrotestosterone inmammals, alopecia, acnes, hypertrophy of prostate and prostatic cancer,which comprises the administration of an effective amount of a compoundof the formula (Ia) depicted in claim 1 or non-toxic salts thereof.
 3. Acompound of the formula (1b): ##STR157## wherein Z is pyrrole includednitrogen substituted by R⁴, thiophene, furan, imidazole includednitrogen substituted by R⁴, thiazole, oxazole, triazole includednitrogen substituted by R⁴, in whichR⁴ is hydrogen, C1-4 alkyl, phenylor phenyl(C1-4)alkyl; A is bond, C1-6 alkylene or C2-6 alkenylene; E isbond or C1-6 alkylene; D is benzene, C4-7 cycloalkane, naphthalene,benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane, ##STR158##in which m is 0 or 1, or benzene fused 4-7 membered heterocylic ringconsisting of one nitrogen, one sulfur or one oxygen atom; R is hydrogenor C1-4 alkyl, R² is hydrogen or C1-4 alkyl; n is 1-3 R³ each,independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro,methylthio, trifluoromethyl or cyano, (2) --Q--T--U--R⁵ in which Q isbond or C1-6 alkylene; T is bond, --O--, ##STR159## --S--, --S₂, --NR⁷-- or --NR⁷ CO--, in which R⁷ is hydrogen, C1-4 alkyl, phenyl orphenyl(C1-4)alkyl and nitrogen atom in --NR⁷ CO-- may be connected with--Q-- or --U--; U is bond, C1-6 alkylene, C2-6 alkenylene, C2-6alkynylene or C1-6 alkylene --O--, in which oxygen atom can be connectedwith R⁵ only; R⁵ is (i) C4-7 cycloalkyl, (ii) phenyl, (iii)diphenylmethyl or (iv) 4-7 membered heterocyclic ring consisting of onenitrogen, one sulfur or one oxygen, or the benzene fused 4-7 memberedheterocyclic ring consisting of one nitrogen, one sulfur or one oxygen,or rings in (i), (ii), (iii), (iv) of R⁵ may be substituted by 1-3 ofC1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro orCOR⁶, in which R⁶ is C1-4 alkyl, NR⁸ R⁹, in which R⁸ and R⁹ each,independently, is hydrogen or C1-4 alkyl; or --Q--T--U--R⁵ is C7-10alkyl, C7-10 alkoxy; or non-toxic salts thereof, with the proviso that,(a) compounds wherein(i) T is --O--, or --NR⁷ --, and U is bond and R⁵is diphenylmethyl in --Q--T--U--R⁵ represented by R³, when Z isthiophene, E is bond and D is benzene or naphthalene, (ii) T is --O--,or --NR⁷ --, and U is C1-6 alkylene and R⁵ is phenyl or diphenylmethylin --Q--T--U--R⁵ represented by R³, when Z is thiophene, E is bond and Dis benzene or naphthalene, are excluded; (b) at least one R³ of (R³)_(n)is a substituent selected from group (2) that is --Q--T--U--R⁵, when Eis bond and D is benzene; (c) all R³ of (R³)_(n) are not hydrogen at thesame time, when E is bond and D is C4-7 cycloalkane, or E is methyleneand D is benzene; (d) 2- 5-2-chloro-4-(1H-pyrrol-1-yl)benzoyl!thiophen-2-yl!acetic acid and methylester thereof and 2- 5-2-chloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)benzoyl!thiophen-2-yl!aceticacid and methyl ester thereof are excluded; (e) when Z is pyrroleincluded nitrogen substituted by R₄, pyrrole is substituted on 2position by ##STR160##
 4. A compound according to claim 3, where in Z ispyrrole included nitrogen substituted by R⁴, in which R⁴ is the samemeaning as defined in claim
 3. 5. A compound according to claim 3, wherein Z is thiophene.
 6. A compound according to claim 3, where in Z isfuran.
 7. A compound according to claim 3, where in Z is imidazoleincluded nitrogen substituted by R⁴, in which R⁴ is the same meaning asdefined in claim
 3. 8. A compound according to claim 3, where in Z isthiazole.
 9. A compound according to claim 3, where in Z is oxazole. 10.A compound according to claim 3, where in Z is triazole includednitrogen substituted by R⁴, in which R⁴ is the same meaning as definedin claim
 3. 11. A compound according to claim 3, where in D is benzene.12. A compound according to claim 3, where in D is C4-7 cycloalkane. 13.A compound according to claim 3, where in D is naphthalene,benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane or##STR161## in which m is 0 or
 1. 14. A compound according to claim 3,wherein D is benzene fused 4-7 membered heterocyclic ring containing onenitrogen, one sulfur or one oxygen atom.
 15. A compound according toclaim 3, which is selected from the group consisting of2-5-(4-t-Butylcyclohexaylcarbonyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenylcyclohexylcarbonyl)-1-methylpyrrol-2-yl!acetic acid, and 2-5-3-(1,2,3,4-Tetrahydro-2-naphthyl)propylcarbonyl!-1-methylpyrrol-2-yl!aceticacid.
 16. A compound according to claim 3, which is2-5-(4-Phenylbenzoyl)-2-thienyl!acetic acid, or 2-5-(4-Phenoxybenzoyl)-2-thienyl!acetic acid.
 17. A compound according toclaim 3, which is2- 5-(4-Phenylbenzoyl)-2-furanyl!acetic acid.
 18. Acompound according to claim 3, which is2-2-(4-Phenylbenzoyl)-1-methylimidazol-5-yl!acetic acid, or2-(4-Phenylbenzoyl)-1-methylimidazol-5-yl carboxylic acid.
 19. Acompound according to claim 3, which is selected from the groupconsisting of2- 5- 4-(4-Ethylphenyl)benzoyl!-1-methylpyrrol-2-yl!aceticacid, 2- 5-(4-Cyclohexylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Benzylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Benzoylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Benzoylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Phenoxybenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenoxybenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Benzyloxybenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Ethylbenzyloxy)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Isopropylbenzyloxy)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Butylbenzyloxy)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-t-Butylbenzyloxy)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenylbenzyl)carbonyl-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Benzyloxy-4-methoxybenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Benzyloxy-2-methylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Benzyloxy-2,3-dimethylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Phenylpropyl)carbonyl-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenylbutyl)carbonyl-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Heptylphenyl)benzoyl-1-methylpyrrol-2-yl!acetic acid, 3-5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl!-2-propenoic acid, 3-5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl!propionic acid, 4-5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl!butanoic acid, 2-5-(4-Phenylbenzoyl)-1-benzylpyrrol-2-yl!acetic acid, 5-5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl!pentanoic acid, 4- 5-4-(4-isopropylbenzyloxy)benzoyl!-1-methylpyrrol-2-yl!butanoic acid, 5-5- 4-(4-isopropylbenzyloxy)benzoyl!-1-methylpyrrol-2-yl!pentanoic acid,2- 5-(2-Phenoxybenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Cyclohexyloxybenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Nitrophenyloxy)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Diphenylmethylaminobenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Dibenzylaminobenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Dibenzylaminomethylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Phenylcarbonylaminobenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenylcarbonylaminobenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenylthiomethylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Phenylthiomethylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenylsulfonylmethylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Phenylsulfonylmethylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(2-Phenylethyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(2-Phenylethynyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(2-Phenyletheneyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5-(5-Phenylpentylcarbonyl)-1-methylpyrrol-2-yl!acetic acid, 2- 5-3-(Pyrrol-1-yl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(Pyrrol-1-yl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(Isoindol-2-yl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(2,5-Dimethylpyrrol-1-yl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5- 3-(2-Thienyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(2-Thienyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(5-Bromo-2-thienyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Heptylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Propylcyclohexyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Methylphenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(2-Methylphenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Propylphenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Methoxyphenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Fluorophenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(4-Chlorophenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(3-Chloro-4-fluorophenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5- 4-(3-Trifluoromethylphenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid,2- 5- 4-(4-Trifluoromethylphenyl)benzoyl!-1-methylpyrrol-2-yl!aceticacid, 2- 5- 4-(3-Nitrophenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid,2- 5- 4-(4-Methylcarbonylphenyl)benzoyl!-1-methylpyrrol-2-yl!aceticacid, 2- 5-4-(4-Dimethylaminocarbonylphenyl)benzoyl!-1-methylpyrrol-2-yl!aceticacid, 5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl carboxylic acid,5-(4-Phenylbenzoyl)-1H-pyrrol-2-yl carboxylic acid, 2- 5-4-(4-Bromophenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Phenylbenzoyl)-1H-pyrrol-2-yl!acetic acid, 2- 5-4-(2,4-Dichlorophenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2- 5-4-(3,5-Dichlorophenyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5-(3-Methyl-4-phenylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2- 5- 4-(N-methyl-N-phenyl)carbamoyl!benzoyl!-1-methylpyrrol-2-yl!acetic acid,2- 5- 4-(N-phenylcarbamoyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5- 4- N-(diphenylmethyl)carbamoyl!benzoyl!-1-methylpyrrol-2-yl!aceticacid, 2- 5- 4-(N-methyl-N-benzyl)carbamoyl!benzoyl!-1-methylpyrrol-2-yl!acetic acid,2- 5- 4-(N-benzylcarbamoyl)benzoyl!-1-methylpyrrol-2-yl!acetic acid, 2-5- 4-(2-phenoxyethoxy)benzoyl!-1-methylpyrrol-2-yl!acetic acid, and 2-5-(3-phenylpropanoyl)-1-methylpyrrol-2-yl!acetic acid.
 20. A compoundaccording to claim 3, which is 2-5-(2-Naphthyl)carbonyl-1-methylpyrrol-2-yl!acetic acid, or 2-5-(9-Oxofluoren-2-yl)carbonyl-1-methylpyrrol-2-yl!acetic acid.
 21. Acompound according to claim 3, which is2-5-(2-benzothienyl)carbonyl-1-methylpyrrol-2-yl!acetic acid, or 2-5-(2-benzofuranyl)carbonyl-1-methylpyrrol-2-yl!acetic acid.
 22. Apharmaceutical composition according to claim 1, which is selected fromthe group consisting of2- 5-(4-Methylbenzoyl)-1-methylpyrrol-2-yl!aceticacid, 2- 5-(4-t-Butylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(3,5-Di-t-butylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Hexyloxybenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Trifluoromethylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Isobutylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-Nitrobenzoyl)-1-methylpyrrol-2-yl!acetic acid, 2-5-(4-isopropyloxybenzoyl)-1-methylpyrrol-2-yl!acetic acid, and 2-5-benzylcarbonyl-1-methylpyrrol-2-yl!acetic acid.
 23. A compound whichis2- 5-(4-Iodobenzoyl)-1-methylpyrrol-2-yl!acetic acid.
 24. A compoundwhich is selected from the group consisting of 2-4-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl!acetic acid,4-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl carboxylic acid, and4-(4-Phenylbenzoyl)-1H-pyrrol-2-yl carboxylic acid.